DE1210825B - Process for the production of 11, 12-epithio-steroids of the Pregnan series - Google Patents

Description

GERMAN

PATENT OFFICE

EDITORIAL

German class: 12 ο - 25/05

Number:
File number:
Registration date:
Display day:

1 210 825
S85275IVb / 12o
17th May 1963
17th February 1966

The present invention relates to a process for the production of 11,12-epithio-steroids the Pregnanreihen, which is characterized in that a corresponding 11 ^ -Thiocyan-12a-hydroxy- or llß-hydroxy-na-thiocyan compound in a manner known per se, optionally with intermediate protection of those present in the molecule, groups which are not inert under the reaction conditions, treated with an acylating agent and the acylated thiocyanohydrin obtained in a manner also known per se with a basic means implemented.

The thiocyanhydrins used as starting materials for the process according to the invention, ie the 11 β -thiocyan-12a-hydroxy or 11 / S-hydroxy-12a-thiocyan steroids of the pregnane series have one of the following sub-formulas:

OH

SCN

NCS

and HO

The thiocyanhydrins include e.g. B. the steroids with one of the following formulas:

CH ₃

and

HO

where A and A 'each have a methylene group, a carbonyl group, a ketalized carbonyl group, such as a lower alkylenedioxymethylene, e.g. B. the ethylenedioxymethylene, propylenedioxymethylene group or a di (lower) alkoxymethylene group, e.g. B. the dimethoxymethylene or diethoxymethylene group, an oxymethylene group or an acylated oxymethylene group such as a lower alkanoyloxymethylene, z. B. the acetyloxymethylene, propionyloxymethylene or butyryloxymethylene group mean; a double bond can be between the 5-position and the adjacent position this must be present.

Process for the production of
11,12-epithio-steroids of the pregnane series

Applicant:

Shionogi & Co., Ltd., Osaka (Japan)

Representative:

Dr.-Ing. Dipl.-Ing. R. Poschenrieder

and Dr.-Ing. Dipl.-Ing. E. Boettner,

Patent attorneys,

Munich 8, Lucile-Grahn-Str. 38

Named as inventor:

Taichiro Komeno,

Junichi Kawanami, Osaka (Japan)

Claimed priority:

Japan May 18, 1962 (20592)

According to the invention, the starting thiocyanohydrin is acylated in a manner known per se subjected using an organic or inorganic acylating agent such as inorganic acylating agent, such as a halogenating agent, z. B. thionyl chloride, thionyl bromide, phosphorus oxychloride, phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride, one Lower alkanoylating agent, e.g. B. acetic anhydride, propionic anhydride, acetyl chloride, Propionyl chloride, a benzoylating agent, e.g. B. benzoyl chloride, benzoyl bromide, a lower alkanesulfonylating agent, z. B. methanesulfonyl chloride, ethanesulfonyl chloride, a benzenesulfonylating agent, z. B. benzenesulfonyl chloride, benzenesulfonyl bromide, or a lower alkylbenzenesulfonylating agent, z. B. toluenesulfonyl chloride, xylene sulfonyl chloride. Although the acylating agents mentioned can be used equivalently is the use of a lower alkanesulfonylating agent or lower alkylbenzenesulfonylating agent the most common. If these usual means can be used the reaction by treating the thiocyanohydrin with the acylating agent in the presence of a condensing agent,

z. B. pyridine, picoline, triethylamine, at room temperature, that is at 10 to 30 ⁰ C, or with ice cooling.

609 508/323

The acylated thiocyanohydrin thus obtained is then subjected, in a manner likewise known per se, to a treatment with a basic agent in order to form an epithio bond. As a basic agent, alkali metal hydroxide, e.g. B. sodium hydroxide, potassium hydroxide, an alkaline earth metal hydroxide, e.g. B. calcium hydroxide, barium hydroxide, an alkali metal hydride, e.g. Lithium aluminum hydride, lithium borohydride, sodium borohydride, and the like can be used. The reaction can be carried out by heating the acylated thiocyanohydrin with said basic agent in a suitable solvent, e.g. B. methanol, ethanol, ether, tetrahydrofuran, dioxane, if necessary under reflux, are heated. While the reaction at room temperature, that is, can be done at 10 to 3O ⁰ C, generally a longer time to complete the reaction is necessary.

If any substituent on the steroid structure other than those in the 11- and 12-positions, are attacked somehow undesirably in the course of the reactions listed above, such Substituents before carrying out the reactions and, if such a requirement arises, on protected in the usual way.

The 1 Iß, 12 / S-Epithk> or lla, 12a-epithio-steroids of the Pregnan series one of the following sub-formulas:

and

The 11 / 3,12 / J-epithio- or lla, 12a-epithio-steroids the Pregnan series include z. B. the steroids with one of the following formulas:

CH ₃

CH ₃

and

wherein A and A 'are as defined above; a double bond may exist between the 5-position and position adjacent to it. As examples of these 11 / 3,12,8-epithio- or 11a, 12a-epithio-steroids of the pregnane series, the following compounds can be mentioned: lla, 12a-epithio-5a-pregnane, 3a-hydroxy-l la, ^ a- epithio-S / S-pregnan, Sß-hydroxy-llajOa-epithio-Sa-pregnan, 3 / 3.20 / S-dihydroxy - 11α, 12α - epithiö - 5a - pregnan, 3 / 3.20 / 3 - diacetyloxy- lla, 12a-epithio-5a-pregnan, 3,3,20,8-diacetyloxy -11α, 12α - epithio - 5β -pregnane, 3.20 - dioxo-11α, 12α - epithio - 5a -pregnane, 3.20 - Dioxo - 11a, 12a-epithio-5 / S-pregnan, 3,20-Dioxo-lla, 12a-epithio-4 - pregnen, 3,3 - ethylene - dioxy - Ila, l2a - epithio-5-pregnen, 11 / 3.12 /? - Epithio-5a-pregnan, 3a-hydroxy -11 / 3.12.8 - epithio - 5ß - pregnan, 3/3 - hydroxy-11 / 3.12 / 3 - epithio - 5 α - pregnan, 3,3,20 / 3 - dihydroxy-H / 8,12 / ⁵ - epithio - 5a - pregnan, 3 / 3,20,8 - diacetyloxy-11 / 3,12,8 - epithio - 5a - pregnan, 3 / 3,20,8 - diacetyloxy-11 / 3,12 / 3 - epithio - 5ß - pregnan, 3.20 - dioxo - 11/3, U / S-epithio-Sa-pregnan, 3,20-dioxo- ll / 3,12 / 3-epithio-5 / S-pregnan, S ^ O-Dioxo-ll ^ n / S- epithio-i-pregnen or 3,3 - ethylenedioxy: 11 / 3,12 / 3 - epithio - 5 -pregnen.

The 11/3; 12,8-epithio- or lla, 12a-epithio-steroids of the pregnane series generally have an anti-DOCA (deoxycorticosterone acetate) activity. For example, 3 / S, 20/3-dioxy-ll ^, 12ß- epithio-5a-pregnan the inhibition of the reflex which is caused by 10 μg DOCA if the compound produced according to the invention is administered subcutaneously in a dose of 5 mg per rat weighing 140 to 160 g. Other 11,12-epithiopregnans have one From this it can thus be concluded that the compounds produced according to the invention are useful as anti-DOCA agents.
The process according to the invention is explained in more detail below by means of a few examples.

example 1

A solution of 1.1 g of 3,20-dioxo-II / S-thiocyan-12a-oxy-4-pregnen in 10 ml of pyridine is mixed with 1 ml of methanesulfonyl chloride and the mixture obtained at room temperature, that is from 10 to 30 ^° C, left to stand overnight. The reaction mixture is then poured into ice water and shaken with ether. The water layer is then shaken with chloroform and the chloroform layer dried and evaporated; 820 mg of a dark red oil are obtained. The oil is purified by chromatography and crystallized from a mixture of ether and chloroform, and yields 3,20-dioxo-11/3-thiocyano-12a-methanesulfonyloxy-4-pregnene in the form of prisms having mp = 158-160 ⁰ C.

1.5 g of the above are added to a solution of 1.5 g of potassium hydroxide in 30 ml of methanol 3,20-dioxo-11/3-thiocyan-12a-methanesulfonyloxy-4-pregnens added, and the resulting mixture is then allowed to stand at room temperature overnight. The reaction mixture is "mixed with water and with a 4: 1 mixture of ether and chloroform shaken. The organic solvent layer is washed with water and evaporated and yields 911 mg of an oily substance. This oily substance is chromatographed on 27 g of clay and eluted with benzene then with benzene-chloroform (9: 1). The eluate is then out Acetone crystallizes and after recrystallization from methanol there are 362 mg of 3,20-dioxo-II / 3, 12,8-epithio-4-pregnen in the form of stalks with a temperature of 170.5 to 172 ° C.

Example 2

To a solution of 536 mg of 3,20-dioxo-II / S-thiocyan-i2a-oxy-5,8-pregnane in 5.3 ml of pyridine, 0.5 ml of methanesulfonyl chloride are added while cooling with ice, and the resulting mixture is left to stand at room temperature overnight. Then water is added, whereby crystals form. The precipitated crystals are filtered, washed with water and then with methanol and recrystallized from acetone and yield 238 mg 3.20 - Dioxo -11/3 - thiocyanato - 12a - methanesulfonyloxy-5,8-pregnane in the form of cubic crystals with F. = 208 to 209 ⁰ C (decomposition).

In a solution of 100 mg of potassium hydroxide in 2 ml of water, 135 mg of the 3.20 - dioxo - 11/3 - thiocyan - 12a - methanesulfonyloxy-5 / S-pregnans prepared above are suspended and the suspension obtained is gently heated and heated for a short period of time then left at room temperature overnight. The reaction mixture is mixed with water and shaken with ether. The ether extract is then washed with water, dried over anhydrous sodium sulfate and evaporated to give 150 mg as a yellow oil. The oil is crystallized from methanol to give 77 mg of 3,20-dioxo-ll / ?, 12, S-epithio-5/5 pregnan in the form of platelets with mp = 152-153 ⁰ C.

Example 3 ' ⁵

To a solution of 1.5 g of 3 / ?, 20 /? - diacetyloxyl /? - thiocyan-12a-oxy-5a-pregnane in 13 ml of pyridine, 1.6 ml of methanesulfonyl chloride are added while cooling with ice, and the resulting mixture is added at room temperature left to stand overnight. The reaction mixture is then mixed with water and shaken with a 1: 4 mixture of chloroform and ether. The organic solvent layer is then washed with water, dried and evaporated to give 2.1 g of an oily substance. This is crystallized from acetone and gives 1.0 g of 3 / 3.20 / 3 -diacetoxy-1 lβ- thiocyan-12a-methanesulfonyloxy-5a-pregnane in the form of prisms with a temperature of 188 to 189 ° C (decomposition).

_{393 mg of the 3 ^, 2O 1} S - diacetyloxy -1 l / S - thiocyan - 12a - methanesulfonyloxy-5a-pregnans, prepared above, are added to a solution of 2 g of potassium hydroxide in 40 ml of methanol, and the mixture obtained is added for 2 hours at reflux heated. The reaction mixture is then mixed with water and concentrated under reduced pressure to remove the methanol. The resulting solution is then shaken with a 1: 4 mixture of chloroform and ether. The organic solvent layer is washed with water, dried and evaporated to give 325 mg of an oily substance. This oily substance is crystallized from methanol and gives 190 mg 3 / ?, 20ß-Dioxy-11 / ?, 12 / Ö - epithio - 5a - pregnane in the form of thick platelets with F. = 158 to 160 ³ C.

110 mg of the S ^ O / S-dioxy-II & nß-epithio-5a-pregnans thus produced are heated on a steam bath with 1 ml of acetic anhydride and 2 ml of pyridine for 2 hours. The reaction mixture is then treated in the usual way and the product obtained is crystallized from ether and yields 108 mg 3 / 3.20 / 9 - diacetyloxy -1 l / S, 120-epithio-5a-pregnane in the form of crystals with F. = 174 up to 176 ° C.

Example 4

55

760 mg ^ ß / y
5a-pregnane and 250 mg of p-toluenesulfonic acid are dissolved in a mixture of 24 ml of acetic acid and 13 ml of acetic anhydride, and the resulting solution is left to stand at room temperature for 3 days. The reaction mixture is then poured into ice water and shaken with a 4: 1 mixture of ether and chloroform. The organic solvent layer is washed successively with water, sodium carbonate solution and finally with water, dried and evaporated. The residue is crystallized from a mixture of ether and petroleum ether and recrystallized from a mixture of acetone and hexane and gives 715 mg of 3 / S, II / ?, 20 / J - triacetyloxy - 12a - thiocyan-5a-pregnane in the form of prisms with F. = 143 to 145 ⁰ C.

A mixture consisting of 605 mg of the 3 ^, 11 / 5.20 ^ - triacetyloxy - 12a - thiocyan-5a-pregnans and 900 mg of potassium hydroxide in 25 ml of 95% ethanol, is refluxed on a steam bath for 2 hours heated. The reaction mixture is then mixed with water and shaken with ether. The ether layer is washed with water, dried over anhydrous sodium sulfate and evaporated. The residue of 388 mg is crystallized from a mixture of methanol and water and recrystallized from a mixture of acetone and hexane and gives 350 mg of 2> β, 20β - dioxy-11α, 12α - epithio - 5a - pregnane in the form of long stalks with F. = 174 to 176 ° C.

110 mg of the 3 ^, 20 ^ -dioxy-lla, 12a-epithio-5a-pregnans thus produced are combined with a mixture of 1 ml of acetic anhydride and 2 ml of pyridine, heated on a steam bath for an hour and then left at room temperature overnight. The reaction mixture and the product obtained are then treated in the customary manner recrystallized from a mixture of acetone and hexane and yields 110 mg 3,3,20 / 3-diacetyloxylla, 12a-epithio-5a-pregnane in the form of stalks with F. = 178 to 179 ° C.

Claims (1)

Claim: Process for the preparation of 11,12-epithiosteroids the Pregnan series, characterized in that one has a corresponding II / S-thiocyan- ^ a-hydroxy or 110-hydroxy-12a-thiocyan compound in a manner known per se, optionally with intermediate protection of those present in the molecule, under the reaction conditions non-inert groups, treated with an acylating agent and the acylated thiocyanohydrin obtained in likewise see, as is known, reacted with a basic agent. Considered publications:
German Auslegeschrift No. 1 036 256;
Chem. Pharm. Bull. [Tokyo], Vol. 8, 1960, p. 672 ff. 609 508/323 2.66 © Bundesdruckerei Berlin