DE1937613A1 - Cyclobutanes esp. steroid spirocyclo butanones - Google Patents

Abstract

Steroid spirocyclobutanones of formula (I): (in which C5 C6 is a single or double bond; V is H or CH3; one of T and U is =O, the other is 2H. A represents the structures (II), (III), (IV) or (V). (where W is H, an alkyl residue of tetrahydro-pyranyl or acyl; Z is H or methyl residue; and R is H, acyl or alkyl, pref. lower alkyl). Cpds. have pharmacological (e.g. testicular- and prostatic- inhibitory, ovulation inhibitory) activity and are intermediates for spironolactones.

Description

Ovolobutanone (addition to patent, patent application P 19 12 236.2) The main patent (patent application P 19 12 236.2) describes steroid spirocyclobutanones of the general formula I, among other things wherein is a single or double bond, V is hydrogen or a methyl group and in which King A has one of the following structures: where W is hydrogen, an alkyl, tetrahydropyranyl or acyl radical, Z is hydrogen or a methyl radical, and R represents a preferably lower alkyl or acyl radical.

Steroid spirocyclobutanones are valuable intermediate products in production of medicines. You can for example by oxidation in the steroid spirolactones be convicted. Steroid spirolactones are of great importance in treatment heart failure.

The compounds of general formula 1 of the main patent are obtained when one on corresponding 17-halo-2o-ketopregnane dimethylmethylene sulfonium oxide can act.

In a further development of the process of the main patent, korde has now been found that the reaction product also contains cyclobutan-2'-ones in addition to cyclobutan-3'-ones. The cyclobutan-2'-ones are isolated by the usual separation processes, for example by chromatography and / or fractional recrystallization.

The invention thus relates to a further development of the process according to the main patent ........ (patent application P 19 12 236.2) for the production of steroid spirocyclobutanones of the general formula II where the ring A, and V have the same meaning as in formula I, due to the action of dimethylmethylene sulfonium oxide on corresponding 17-halo-20-ketopregnane of the general formula III in which X is chlorine or bromine, characterized in that the cyclobutan-2'-one of the formula II is separated off from the reaction product in a customary manner, preferably by chromatography and / or fractional recrystallization.

The invention also relates to compounds of the general formula II It is surprising that in the reaction of a-haloketones with dimethylethylene sulfoniumoid Cyclobutanones arise because it is known that ketones with dimethylmethylene sulfonium oxide Form oxiranes (Journ. Am. Chem. Soc. 84 (1962), pp. 867-868). With regard the cited reference could also have been expected that one from the α-haloketone a, ßunsaturated ketone formed by splitting off hydrogen from halogen to form a Cyclopropyl ketone is methylenated. The formation of cyclobutanones, however, was possible Do not expect it, as it is well known that the tendency towards four-ring formation only is very low.

The new process for the production of cyclobutanones goes under amazingly mild conditions. So it is generally sufficient to add the reaction components in an inert solvent for a time at room temperature or slightly higher Let the temperature stand. For the separation and purification of the isomeric cyclobutanones are the usual methods such as sublimation, chromatography and crystallization applied to '.

The dimethylmethylene sulfonium oxide used as a reagent can be selected from a trimethylsulfoxonium salt, such as the halide, perchlorate or Methyl sulfate, in an aprotic solvent such as dimethyl sulfoxide or dimethylformamide be released with an anhydrous base at room temperature. To carry out of the process according to the invention, it is advantageous to use the dimethylmethylene sulfonium oxide not to isolate, but to react the reaction solution with the α-haloketone further allow.

The inert solvents used in the reaction according to the invention therefore preferably dimethyl sulfoxide and dimethylformamide.

17-Halogen-20-ketopregnane are used as starting materials can, for example, by alkyl and free or functionally modified hydroxyl groups be substituted. Keto groups can also be included. Reactive keto groups such as saturated 3-ketones or unsaturated Al-3-ketones, for example, must be carried out before the implementation be protected by ketalization if one wants to avoid side reactions.

Example 1 3, o g of 17-bromo-3ß-acetoxy-5α-pregnan-20-one in 75 ml of dimethyl sulfoxide with dimethyl sulfoxonium methylide, prepared from 2.94 g trimethylsulfoxonium iodide and 535 mg sodium hydroxide, one hour at room temperature touched.

After stirring into weakly acetic acidic ice water, the precipitate ird filtered off, washed neutral, taken up in methylene chloride and dried. Of the The residue obtained after evaporation is chromatographed on silica gel. It after recrystallization from isopropyl ether, 440 mg of 3β-acetoxy-spiro [5α-pregnan-17,1'-cyclobutanJ-2'-one obtained from melting point 162-164 ° C.

Example 2 32 g of 17-bromo-3ß-acetoxy-5-pregnen-20-one are in 716 ml Dimethyl sulfoxide with dimethyl sulfoxonium methylide, prepared from 32.05 g of trimethylsulfoxonium iodide and 5.83 g sodium hydroxide, stirred for 1.5 hours at room temperature.

It is then worked up as described in Example 1.

After chromatography on silica gel and recrystallization from isopropyl ether 7.4 g of 3ß-acetoxy-spiro [5-pregnen-17,1'-cyclobutane] -2'-one have a melting point Obtained 187-189.5 ° C.

Example 3 3.95 g of 17-bromo-4-pregnen-3,20-dione are dissolved in 115 ml of dimethyl sulfoxide with dimethylsulfoxonium methylide, prepared from 4.4 g of trimethylsulfoxonium iodide and 800 mg sodium hydroxide, stirred for 1.5 hours at room temperature and as in example 1 described worked up. After chromatography on silica gel and Recrystallization from isopropyl ether 380 mg of spiro [4-androstene-17,1'-cyclobutane] -3,2'-dione obtained from melting point 169-177 ° C.

UV: # 241 = 16 600.

Claims (5)

P a t e n t a n s p r ü c h e 1.) Further development of the process according to the main patent .......... (patent application P 19 12 236.2) for the production of steroid spirocyclobutanones of the general formula II wherein a single or double bond, V is hydrogen or a methyl group and in which the ring A has one of the following structures takes: y 1ode Where z Y 1, where y W is hydrogen, an alkyl, tetrahydropyranyl or acyl radical, Z is hydrogen or a methyl radical, and R is a preferably lower alkyl or acyl radical, by the action of dimethylmethylene sulfonium oxide on corresponding 17-halo-2o-ketopregnane of the general formula III in which X is chlorine or bromine, characterized in that the cyclobutan-2t-one of the formula II is separated off from the reaction product in a customary manner, preferably by chromatography and / or fractional recrystallization. 2.) Compounds of the general formula II. 3.) 3β-Acetoxy-spiro [5α-pregnan-17,1'-cyclobutane] -2'-one. 4.) 3β-Acetoxy-spiro [5-pregnen-17,1'-cyclobutane] -2'-one. 5.) Spiro [4-androstene-17,1'-cyclobutane] -3,2'-dione.