CS226540B1 - Method of preparing steroidic 11,12-unsaturated compounds - Google Patents

Description

The present invention relates to a process for the preparation of steroid 11,12-unsaturated compounds of formula I

in which it denotes

R M-O-acetyl, β-O-acetyl or α-O-benzoyl, X hydrogen atom or O-acetyl, ¥ grouping

C00CH ₃

Z Η, 5a-H or 5/3-H, optionally Y and Z, are grouped together

These compounds, which serve as intermediates in the synthesis of some pharmacodynamically active derivatives, are most readily accessible by chemical variations of the natural 12'-hydroxy compounds of formula II

wherein R, X, Y and Z are the same as in Formula I, such as certain bile acids or steroid sapogenin derivatives.

Removal of the hydroxyl group from ^you: steroidal molecule is usually carried out by cleavage of an alkyl- or arylsulfonic acid from the corresponding alkyl- or arylsulfonyloxyesteru. If the hydroxyl group is located in the steroid molecule in a position that is not adjacent to the quaternary carbon atom and thus does not allow the formation of an undesirable skeletal rearrangement, direct dehydration of the 12t-hydroxy derivatives with a pyridine-inorganic chloride complex such as thionyl chloride, phosphorus oxychloride, phosphorous trichloride and the like. Direct dehydration of the 12'-hydroxy compounds is used only exceptionally because the adjacent 12a-hydroxyl group to the quaternary carbon atom at the 13-position allows easy unwanted rearrangements such as the formation of C-nor-D-homo compounds.

A procedure for dehydrating a 12'-hydroxy compound with phosphorus oxychloride and pyridine is described (Nakada, Steroids 2, 45, 1963), but yields of 11,12-unsaturated are unsatisfactory and the purification of the product is hampered by large amounts of ballasts of similar chemical properties. the title compounds favor elimination reactions of sullphonate esters (Chen, Synthesis 1976, 125; Bharucha, Schrenk, Experientia 21, 248, 1965) or thermal decomposition of 12-p-toluenesulfonylhydrazones (Capan, Quart. Reiw. 18, 45, 85, 1964; Bamlford, Stevens, J. Chem. Soc. 1952, 4735], although these reactions represent a number of reaction steps and, moreover, require relatively expensive reagents.

The above disadvantages are eliminated by the process for the preparation of steroid 11,12-unsaturated compounds of the formula I by partial dehydration of the steroid 12-hydroxy compounds of the formula II with a thionyl chloride-pyridine complex according to the invention, characterized in that the reaction is carried out with thionyl chloride-pyridine complex equal volumes of both components at a temperature of from 0 to 15 to 25 ° C containing thionyl chloride in a 3 to 5-fold molar excess, based on 1 mole of the starting steroid 12-hydroxy compound of formula II, in pyridine or an inert aromatic hydrocarbon-type solvent; for example benzene or toluene, at a temperature of from 20 ° C to the boiling point of the reaction mixture, preferably at a temperature of 60 to 80 ° C.

The process of the invention utilizes the possibility of direct dehydration of readily available steroid 12-hydroxy compounds of formula II under the aforementioned conditions, wherein the desired steroid 11,12-unsaturated compounds of formula I can be obtained in satisfactory yield and in sufficiently pure form. Suitably equal volumes of both reagents are used to form the thionyl chloride-pyridine complex. The dehydration reaction is preferably carried out in an inert organic solvent of the aromatic hydrocarbon type, for example benzene or toluene, optionally in pyridine. Aliphatic hydrocarbons, chlorinated and protic solvents are unsuitable for dehydration.

The formation of the thionyl chloride-pyridine complex is preferably carried out at a temperature of up to 0 to 15 to 25 ° C, and dehydration at a temperature of from 20 to 80 ° C. The reaction requires anhydrous conditions and, for starting materials, interfering functional groups must be protected by appropriate substitution. When dehydration is carried out in pyridine as reaction medium, the product is isolated by pouring the reaction mixture into ice water, suctioning off the precipitate, washing it with water until neutral and crystallizing the dry crude product from a suitable solvent. When the aromatic hydrocarbon serves as the dehydration medium, the product is isolated by washing the reaction mixture with water, an alkali metal hydrogen carbonate solution and water to neutrality, drying the organic phase with a suitable desiccant such as anhydrous sodium sulfate, distilling off the solvent in vacuo and crystallizing the residue.

For example, a solution of the starting steroid 12'-hydroxy compound of formula (II) in pyridine is cooled to 0-25 ° C, a calculated amount of thionyl chloride is added, and the reaction mixture is stirred at 20-80 ° C. optionally at boiling point; or a thionyl chloride pyridine complex is first prepared under the conditions described and a solution of the starting material in an aromatic hydrocarbon is added to the complex. Dehydration then proceeds the same as using pyridine as the medium. Suitable solvents for the crystallization of the crude product are lower alkanol solvents, in particular methanol, which very effectively separate the desired material from the reaction by-products.

Further details of the process according to the invention can be seen from the following examples.

Example 1

5 ml of freshly distilled thionyl chloride are added to a solution of 10 g of .alpha.-diacetoxy-1.alpha.-hydroxy-.beta.-oxoic acid methyl ester in 30 ml of pyridine with stirring at room temperature; the reaction mixture was stirred at the same temperature for 4 h and then heated at 70 ° C for 10 min. After cooling, it is poured into 300 ml of ice-water, the precipitated crude product is filtered off with suction, washed with water, dried and recrystallized from methanol. 5.1 g (52% of theory) of methyl 3α, 7α-di-ethoxy-5β-chol-11-enoic acid, m.p. 131-136 ° C, are obtained.

220540

Example 2

To a mixture of 20 ml of toluene, 6 ml of pyridine and 6 ml of thionyl chloride at room temperature is added a solution of 10 g of methyl 3, 7α-dialoxyoxy-12α-hydroxy-5 / S-cialanic acid methyl ester in 60 ml of toluene. at 60 ° C. After cooling, it is washed with water, potassium bicarbonate solution and water, dried over anhydrous sodium sulphate and the solvent is distilled off in vacuo to dryness. Crystallization of the residue from methanol gave 4.8 g of the same material as in Example 1, m.p. 131-135 ° C.

Example 3

To a mixture of 30 ml of benzene, 2.8 ml of thionyl chloride and 2.8 ml of pyridine is added at room temperature with stirring a solution of 5 g of methyl 3-p-benzoyloxy-12, α-hydroxy-5 (3-cholanic acid) in 30 ml of benzene. The reaction mixture was refluxed for 1 h and then treated as in Example 2. 2.4 g of 3-benzoyloxy-5H-chol-11-effioic acid methyl ester, mp 99-102 ° C, was obtained.

Example 4

To a solution of 1 g 3/3-acetoxy-12a-hydroxy-5. ", 20j / 3H, 22! AO, 25/3 H _r-spirostane in 3 mL of pyridine at 0 ° C and under stirring 0.4 ml of thionyl chloride and the reaction mixture was stirred at room temperature for 2 h and at 65 ° C for 1 h. Processing as in Example 1 gave 0.47 g 3i / $ - acetoxy-5, 20 / 3H, 22aO, 25/3 H _{F-spirost-l-ene,} t., T. 200-206 ° C (and _D ²⁰ = -41 °.

Claims (1)

WE'RE GOING ' A process for the preparation of steroid 11,12-unsaturated compounds of formula I OF THE INVENTION by partial dehydration of steroid 12-hydroxy compounds of the general formula II in which R αΐ-O-acetyl, O-O-acetyl, α-O-benzoyl, X hydrogen or O-acetyl, Y grouping O COO CHt> Z is hydrogen, 5a-H or 5, 3-H, optionally Y and Z are joined together by a moiety in which R, X, Y and Z are the same as in Formula I, with a thionyl chloride-pyridine complex characterized in that the reaction is carried out with a thionyl chloride-pyridine complex prepared by interaction of equal volumes of both components at 0 to 15 to 25 ° C, containing thionyl chloride in a three to five-fold molar excess, based on 1 mole of the starting steroid 12-hydroxy compound of formula II, in pyridine or an inert organic aromatic hydrocarbon solvent such as benzene or toluene at 20 ° C to the boiling point of the reaction mixture, preferably at a temperature of 60 to 80 ° C.