JPS6353995B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel intermediates for the production of corticosteroids such as hydrocortisone and prednisolone. 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 drugs, still use progesterone produced from stigmasterol or 16-dehydropregnenolone produced from diosgenin as intermediate raw materials, and also use bile acids as raw materials. Manufactured by a long method. The present inventors have discovered the above-mentioned androst-4-ene-3,17-dione and androst-1,4-diene-3,17-dione, which have recently been supplied in large quantities and at low cost. In addition, androsta-4,9 ⁽¹¹⁾ -diene-3,17, which is easily derived from 9α-hydroxyandrost-4-ene-3,17-dione, which has also recently been produced by fermentation.
- Focused on the fact that corticoids could be produced in a shorter number of steps by using dione as a raw material, and conducted extensive research. As a result, 17β-ethynyl 17α-hydroxyandrost-4-en-3-one, 17β-ethynyl-17α, which is extremely advantageous for producing corticoids.
-Hydroxyandrosta-1,4-diene-3
17β-ethynyl steroids such as -one, 17β-ethynyl-17α-hydroxyandrost-1,4,9 ⁽¹¹⁾ -trien-3-one can now be easily produced. These 17β-ethynyl steroids are new compounds, and corticoids can be produced through relatively short steps as shown in the formula below.

[Table] (In the formula, NBS represents N-bromosuccinimide.) The 17β-ethynyl steroids of the present invention are represented by the following general formula (). (In the formula, the dotted line represents a single bond or a double bond.) From the 17-ketosteroids of the general formula (), by the route shown in the formula below. (In the formula, dotted lines represent single or double bonds.) Manufactured. That is, 17 expressed by the general formula ()
- Ethynylation of the ketosteroid by a method known per se to give a 17α-ethynyl-17β-hydroxysteroid of the general formula (), which is also converted to a steroid of the general formula () by a method known per se with concentrated nitric acid. to lead to a 17α-ethynyl-17β-nitroxysteroid represented by the general formula (). 17α-ethynyl- of general formula ()
When a 17β-nitroxysteroid is hydrolyzed in the presence of a silver salt such as silver nitrate or a copper salt such as cuprous chloride, a 17β-ethynylsteroid represented by the general formula () can be obtained in good yield. To describe in more detail the method for producing 17β-ethynyl steroid of the general formula (), 17α-ethynyl-17β-nitroxy steroid represented by the general formula () is dissolved in an organic solvent containing water, and silver nitrate is added to the 17α-ethynyl-17β-nitroxy steroid. Hydrolyze by adding silver salts such as, copper salts such as cuprous chloride. Organic solvents containing water include, for example, cyclic ethers such as tetrahydrofuran and dioxane, esters such as ethyl acetate, ketones such as acetone, dimethylformamide, dimethyl sulfoxide, and ethylene glycol dimethyl ether, which are mutually soluble in water. It is a mixed solvent of a highly polar aprotic solvent and water. The amount of water is usually
More than 10 times the molar amount of the steroid of general formula () is required. The silver or copper salt used as a catalyst, such as silver nitrate or cuprous chloride, is used in an amount of 0.01 to 1.5 times, preferably 0.05 to 0.7 times, the amount of the steroid of the general formula (). Reaction temperature is -10~100℃, preferably 10~80℃
It is. The present invention will be explained in more detail by way of examples below, but the present invention is not limited by the following examples unless it exceeds the gist thereof. Example 1 17β-ethynyl-17α-hydroxyandroster-1,4-dien-3-one. <Raw material synthesis> 17α-ethynyl-17β-nitroxyandrosta-1,4-dien-3-one. 8.0 g of 17α-ethynyl-17β-hydroxyandrosta-1,4-dien-3-one and acetic anhydride
Add 64ml and cool to -20℃. Add 6.4 ml of fuming nitric acid dropwise and stir at -20°C for 1 hour. Pour the reaction mixture into 500 g of ice water and stir. Filter the precipitated crystals, and dissolve the crystals in ethyl acetate.
The ethyl acetate solution is washed with water, dried, and concentrated to give 8.97g.
17α-ethynyl-17β-nitroxyandrosta-1,4-dien-3-one is obtained. This product can be used as a raw material for the next hydrolysis process without further purification. <Hydrolysis> Add 170 ml of tetrahydrofuran, 30 ml of water, and 2.0 g of cuprous chloride to 25.0 g of 17α-ethynyl-17β-nitroxyandrosta-1,4-dien-3-one, and add 1.5 g of cuprous chloride at 65°C under nitrogen atmosphere. Stir for an hour. After the reaction, add 200ml of benzene and saturated saline to the reaction solution.
Add 200ml and extract the reaction product. The organic layer is separated, washed twice with saturated brine, and dried by adding anhydrous sodium sulfate. Add dichloromethane to the crystals obtained by distilling off the solvent.
250ml, add 250ml of n-hexane and recrystallize.
12.69 g of 17β-ethynyl-17α-hydroxyandrosta-1,4-dien-3-one are obtained. The above crystals are recrystallized from a mixed solvent of benzene and tetrahydrofuran and then from ethyl acetate to obtain pure 17β-ethynyl-17α-hydroxyandrost-1,4-dien-3-one. Melting point: 218-219℃ Specific rotation: [α] ²⁴ _D = +90.9° (C: 1.02, tetrahydrofuran) Mass spectrum: 310 (M ⁺ ) NMR spectrum: ((CD ₃ ) ₂ SO solvent) 18-position H of methyl group δ0.91ppm (3H, S) H of 19-position methyl group δ1.21ppm (3H, S) H of ethynyl group δ2.43ppm (1H, S) Example 2 17β-ethynyl-17α-hydroxyand Rost-4-en-3-one <Raw material synthesis> 17α-ethynyl-17β-nitrooxyandrost-4-en-3-one 20.0 g of ethisterone was suspended in 160 ml of acetic anhydride and cooled to -20°C. Add 16.0 ml of fuming nitric acid dropwise. After stirring at -20°C for 3 hours, slowly pour the reaction mixture into ice water (2000 g) while stirring. An oil separates into a lower layer. This oil is separated and dissolved in 150 ml of ethyl acetate. Some crystals that do not dissolve in ethyl acetate remain, so these are removed. Another crystal was ethisterone (2.9 g). The ethyl acetate layer is washed with saturated brine and dried over magnesium sulfate. When ethyl acetate is distilled off, white crystals are precipitated. Add 100 ml of n-hexane to suspend the crystals, then filter. 17α-ethynyl-
17β-nitrooxyandrost-4-ene-3
- Obtain 17.3 g of on. This product can be used as a raw material for the next hydrolysis process without purification. <Hydrolysis> 17.3 g of the above 17α-ethynyl-17β-nitrooxyandrost-4-en-3-one
(48.4 mmole) in 173 ml of tetrahydrofuran. Next, 30.0ml of distilled water and 8.18g of silver nitrate.
(48.1 mmole) and stir at 23°C for 24 hours.
White crystals precipitate. Add 50 ml of a saturated aqueous ammonium chloride solution and 15.0 g of sodium cyanide to the reaction solution and stir. The white crystals disappear. The reaction product was extracted by adding 150 ml of chloroform, washed with water, and then dried and concentrated to obtain 14.0 g of white crystals. 7.0g of 17β-ethynyl-17α recrystallized from benzene
-hydroxyandrost-4-en-3-one is obtained. The reactant recovered from the recrystallization mother liquor is charged into a column packed with silica gel. Using benzene as a developing solution, 2.35 g of pregna-4,16-diene-20-
In-3-one is obtained. Then benzene(10)−
4.1g of 17β-ethynyl- with a developing solution of ethyl acetate (1)
17α-Hydroxyandrost-4-ene-3-
On was obtained. Recrystallization twice from methanol yields pure 17β-ethynyl-17α-hydroxyandrost-4-en-3-one. Melting point: 201.3-201.8℃ Specific rotation: [α] ²¹ _D = +132.7℃ (C = 1.05, tetrahydrofuran) Mass spectrum: 312 (M ⁺ ) NMR spectrum: (CDCl ₃ solvent) H δ0 of the 18th-position methyl group .91ppm (3H, S) H of 19-position methyl group δ1.20ppm (3H,S) H of ethynyl group δ2.48ppm (1H,S) Reference Example 1 17β-ethynyl-17α- obtained in Example 1
Hydroxyandrosta-1,4-diene-3-
Add 40 ml of benzene, 8 ml of distilled water, 1.12 g of mercuric chloride, and 0.2 ml of aniline to 0.68 g of chlorine, and stir at 60°C for 13 hours. Separate the insoluble matter and wash the collected insoluble matter thoroughly with chloroform. The reaction solution and the chloroform washing solution are combined and the aqueous layer is separated. The organic layer is washed with a 5% aqueous hydrochloric acid solution and then with a saturated sodium bicarbonate solution, and dried by adding sodium sulfate. When the solvent is distilled off, 0.6155g of
17α-Hydroxypregna-1,4-diene-
3,20-dione is obtained. Recrystallization from a mixed solvent of 40 ml of tetrahydrofuran and 10 ml of octane yields 0.499 g of purified 17α-hydroxypregna-1,4-diene-3,20-dione. This product matched the standard in all aspects of high performance liquid chromatography, thin layer chromatography, infrared absorption spectrum, NMR spectrum, and mass spectrum.

Claims (1)

[Claims] 1. The following general formula (In the formula, the dotted line represents a single bond or a double bond.) 17β-ethynyl steroid.