DE1568643A1 - Process for the preparation of 3- (4'-oxo-cyclohexyl) -4- (3'-oxo-cyclohexyl) -hexene-3 - Google Patents

Description

Process for the preparation of 3. (4'-oxo-cyclohexyl) -4- (3'-oxo-cyclohexyl) -hexene-3 It has already been proposed that 3- (4'-oxocyclohexyl) -4- (3'-oxo-cyclohexyl) -hexene-3 from 3- (4'-ethylendoxy-cyclohexyl) -4- (cyclohexen- 3'-yl) -hexen-3 by hydroboration, To produce oxidation and subsequent ketal cleavage (cf.

Patent application F 48 770 IVb / 12 o (Fw 5021 A)).

It has now been found that this compound can be prepared in a simpler way and in better yields if one uses cyclohexane-carboxylic acid esters of the general formulas II and IIa in which 21 and R2 always have the same meaning and either two hydrogen atoms or two methyl groups *) and R3 are a lower alkyl radical, are subjected to a mixed acyloin condensation with each other in the presence of alkali metals, the resulting reaction mixture is oxidized and the resulting diketone mixture is the unsymmetrical Compound of the general formula III acetylide or acetylenmagabseparated, it then reacts with lithium nesium halide, the resulting llexadiyne compound of the formula IV with diphosphorus tetraiodide in the presence of carbon disulfide and tertiary organic bases, the resulting compound of formula V *) and an open or ring-shaped ketal group of mono- or dihydric alpha alcohols with Diiniid to the Ilexen compound of the formula VI reduced and the compound of formula VI thus obtained is reduced with alkali metals in ammonia or primary aliphatic amines in the presence of alcohol, then treated with acid and oxidized.

The alkyl cyclohexanecarboxylates used as starting materials are by ketalization of 4- or 3-oxocyclohexanecarboxylic acid esters in itself obtained in a known manner, (see. Also Example 1a)). this is the 4-oxocyclohexanecarboxylic acid ester with, for example, urenzcatechol, the 3-oxo-cyclohexanecarboxylic acid ester with bivalent alcohols such as ethylene glycol, propylene glycol or neopentyl glycol. You can also use t-valent aliphatic alcohols such as methanol or ethanol open ketals are formed. The carboxylic acid esters are in particular ethyl, Methyl or n-propyl ester in question. For the acyloin condensation of the two cyclohexanecarboxylic acid esters of formula II and IIa works one advantageous with an excess one component (II or IIa). The condensation takes place in the presence of alkali metals, in particular sodium metal instead, with either aromatic hydrocarbons as solvents such as benzene, toluene or xylene or ethers, for example diethyl ether as well Tetrahydrofuran or dioxane can be used. The reaction temperatures are dependent on the chosen solvent and on the choice of alkali metal. Advantageous one works at temperatures between 20 and 70 ° C, with the exclusion of oxygen, mostly under a nitrogen atmosphere. The reaction is generally after a few hours completed. It is advantageous to work in the presence of finely divided alkali metals with sodium dust.

After working up in the usual way, the reaction mixture obtained is which consists of the symmetrical and asymmetrical keto alcohols is oxidized. as Oxidizing agents are advantageously used, with particular preference, metal oxides Hydroxide. For example, lead dioxide or manganese dioxide can also be used. Pyridine, dimethylformamide or aromatic solvents are used as solvents for the oxidation Hydrocarbons such as benzene or toluene are used. The oxidation can ever can be carried out at the choice of the oxidizing agent at citeller's temperature, one can even at elevated temperatures, up to the boiling point of the solvent used, oxidize.

The reaction mixture obtained, which consists of a mixture of the two symmetrical Diketone and the asymmetrical Uiketone III is then separated. Here one can obtain the main amount of the symmetrically with pyrocatechol by crystallization separate ketalized diketones. The remaining reaction mixture after separation this diketone is advantageously separated by chromatography. That way Smooth separation of the diketone III essentially enables the successful Implementation of the invention Procedure for creation the unbalanced connection I.

The process product of the general formula III is in a subsequent Reaction with lithium acetylide or acetxylene magnesium halide to form the hexadiyne derivative of the formula IV, with acetylene magnesium halides in ethers, in particular Diethyl ether or tetrahydrofuran works, while lithium acetylide does not can only work in ethers, but also in liquid ammonia. It is advisable a larger excess of acetylidene in order to achieve complete conversion. It is advantageous to drop the solution of the diketone of the formula III, dissolved in an ether, to the acetylide solution and then refluxed for several hours.

The resulting hexadiyne compound of the formula IV is then with diphosphorus tetraiodide in the presence of carbon disulfide and tertiary organic Bases converted into the llexen-diyne compound of the formula V. The + diphosphorus tetraiodide can be as described in Example 1, from iodine and yellow phosphorus in absolute Making carbon disulfide. The reaction with the reagent dissolved in carbon disulfide, is generally carried out at room temperature, usually several hours required.-It is also possible to work at a slightly elevated temperature1, however it is advisable not to heat above 00 C. The reaction mixture is customary Work-up purified by chromatography on aluminum oxide.

For the subsequent diimide reduction to the liex derivative of the formula VI can be the diimide 112N2 from azodicarboxylic acid or from toluenesulfonylhydrazine (cf. e.g. J.Am.Chem.

Soc. 83, pp. 3725 and 3729 (1961)). be for example are added to a solution of the compound V in an inert organic solvent such as benzene, which is advantageous with a lower aliphatic alcohol such as methanol or ethanol mixed is dry potassium salt of azodicarboxylic acid and add an acid dropwise to this reaction mixture while being clocked. Advantageous glacial acetic acid is used, which is mixed with the same solvent, e.g. benzene and Methanol, is mixed. It is advantageous to work at room temperature and stir until the reaction solution has discolored. Then it is neutralized, for example with soda or bicarbonate solution, and the organic layer in the usual way Way worked up. The oily crude product obtained is advantageously chromatographed cleaned.

Finally, the hexene derivative of the formula VI obtained in this way is in one 1 Birch reaction ", i.e. with alkali metals in ammonia or primary aliphatic Amines, reduced. it is necessary to use excess alcohol during the reduction cadie. 5 times the amount to be added, since only under these conditions the aromatic Ring of the drone catechol valley is hydrogenated.

Then, e.g. by means of mineral acids or strong organic ones Acids) and then hydrolyzed with metal oxides, preferably chromium trioxide oxidized by the partially or fully reduced to the alcohol group in the reaction To convert 3-keto group back into a keto group. As a solvent for the Oxidation are pyridine, dimethylformamide or aromatic hydrocarbons, like e.g. I3. Benzene or toluene is used.

The process product is characterized by an unexpected androgenic, gestagenic, anti-inflammatory and anabolic effects and can therefore be used as a pharmaceutical be used.

It is also used as an intermediate in the manufacture of pharmaceuticals. x) (based on the substance used) Example 1 a) Representation of 4,4-dioxybenzene-1'-2-cyclohexane-carboxylic acid ethyl ester Corresponding to the ketalization of cyclohexanone according to Birch, J. Chem. Soc. 1947, 102 a solution of 30 g of 4-oxocyclohexane-carboxylic acid ethyl ester, 21.5 g pyrocatechol and a spatula tip of p-toluenesulfonic acid in 300 ccm absol.

Benzene heated under reflux on a water separator until no more water separates. The solution is mixed with ice-cold 5 percent. aqueous sodium hydroxide solution washed until the aqueous phase is only slightly colored. After the usual work-up gives the isolated oily crude product after bulb tube distillation (bp (0.2-0.4 mm) 130-140 °) 33.74 g (73%) crystals which dissolve at room temperature.

IR spectrum as O1: 5.76 u (1736 cm-1) Dstercarbonyl band 8.06 u (1241 cm-1), aryl ketal band b) Acyloin condensation To 18.5 g of dispersed sodium in 500 ccm absolute The mixture of 68.80 g of the ketal ester obtained according to a) becomes ether with 25.66 g of 3-ethylenedioxy-cyclohexanecarboxylic acid ethyl ester in 500 ccm absol. ether added in portions under a nitrogen atmosphere within 3-4 hours, while the reaction solution is heated to gentle boiling. After heating for a further 3 hours left to stand overnight at room temperature, decanted from the excess Sodium, which is decomposed with a little methanol. To the subsequently united 300 cc ammonium chloride solution are added to organic oil phases, the aqueous phase extracted with ether and then washed neutral with ammonium chloride solution. c) Oxidation of the reaction mixture to the corresponding diketones and isolation of 1- (4 ', 4'-dioxybenzene-1 ", 2" -cyclohexyl) -2- (3,3-ethylenedioxy) -dioxoethane.

70.8 g of oily crude product can be used in 500 com absolute Dissolved pyridine, to which 56.8 g of chromium trioxide in 660 cc of pyridine were prepared Oxidation mixture (cf. Liebigs Ann. 684, 24 (1965) given and stirred over To be left at room temperature overnight.

For working up, it is filtered through a column of 15 × 8 cm aluminum oxide 1 that comes with a cn. 15 com high layer of coarse-grained activated carbon overlaid is and extracted with ethyl acetate.

After the solvent has been stripped off in vacuo, the largest crystallizes Part of the syiruuetric diketone ketalized in the 4,4-position from ether. That Remaining mixture can be applied to 1.5 mm thickly coated plates with silica gel Cyclohexane / methylene chloride / ethyl acetate 10: 4: 2 has been separated as the eluent, with up to 3 g per 1 m sheet can be applied. A total of 15.60 8 is obtained (46.5% yield, based on 3,3-ketal ester) of the unsynunetric product of the formula III.

The substance crystallized from ether melts at 99.1020 mass spectrum C22 H26 06 I calc. 3864 found. 386 IR spectrum (KBr): 5186 µ (1706 cm) carbonyl band 8.06 µ (1241 cm-1) aryl ketal end, 9.18 µ (1089 cm-1) ethylene ketal band, UV spectrum (Methanol): 283 mp (# = 4500), shoulders at 290, 238 mµ 230 mµ (# = 3300) d) Acetylene Grignard to 3- (4 ', 4-dioxybenzene-1 ", 2" -cyclohexyl) -4- (3'-ethylenedioxy-cyclohexyl) -hexadiyne-1, 5-diol-3,4 (IV) tetrahydrofuran From 25.1 g of magnesium shavings in 100 ccm abs. and 83 cc of ethyl bromide in 300 cc of tetrahydrofuran is first prepared a reagent solution, those saturated with acetylene after filling up with tetrahydrofuran to 600 cc to 400 cc Tetrahydrofuran is added dropwise. During the implementation at approx. 50 and for a further 30 minutes acetylene through the solution. Afterward the solution of 35 g of diketone III in 100 cc of tetrahydrofuran is added dropwise and the mixture is heated 2 hours under reflux. For work-up, with ice-cooling with saturated Amnion chloride solution decomposed, the organic phase separated and the aqueous phase extracted with benzene. After further customary work-up, an oily, foamy product is obtained Product from which 8.24 g of crystalline product are obtained after spraying with ether was preparative. The mother liquor yields after purification by thin layer chromatography (Cyclohexane / ethyl acetate 1: 1) 19.58 g of pure product, corresponding to a total yield of 70% of compound IV. The substance digested with ether melts at 195 - 197 ° (Kofler) Elemental analysis C26 H30 06 (438): C ii calc. 71.21 6.90 found. 71.10 6.99 IR (KBr): 2.86 µ (3497 / cm) hydroxyl band 3.06 µ (328 / cm) #acetylene bands 4.74 µ '(2110 / cm) 6.14 µ (1629 / cm) # C = C double bond bands 6.24 µ (1603 / cm) 8.07 µ (1239 / cm) aryl ketal band 9.33 Pl (1072 / cm) ethylene ketal band e) Dehydration with P2J4 to give 3- (4'-dioxybenzene-1 "-2" -cyclohexyl) -4- (3'-ethylenedioxy-cyclohexyl) -hexadiyne-1, 5-en-3 (V) At 66.2 g in 800 ccm abs. Iodine dissolved in sulfur is added Stir 8.30 g of white phosphorus, let stand for about 30 min. At room temperature until the Solution is colored light red, the solution is filtered and mixed with 27.82 g in abs. Pyridine dissolved diol IV.

After a reaction time of 4 hours at room temperature, the distillation is carried out Solvent up to about 1/3 of the volume in a water jet vacuum, with diet temperature should not exceed 400. The alkaline with 5% aqueous sodium hydroxide solution made reaction solution is extracted with, the organic phase with Tiliosulfat- and sodium chloride solution washed to pH 7 and worked up as usual.

23.27 g of brown-colored crude product are over 600 g of aluminum oxide Woelm II filtered with benzene and give 9.23 g (34.7 X of theory) of crystalline diyne (V).

In the thin layer with cyclohexane / ethyl acetate 5: 1 as solvent the product turns out to be almost uniform. The melting point is 160-164 (Kofler).

IR (KBr): 3.05 µ (3279 / cm) acetylene band 6.13 p (1631 / cm) 6.24 p µ (1603 / cm) # CIC double bond bands 8.07 p (1239 / cm) aryl ketal band 9.34 p (1071 / cm) Ethylene ketal band UV (methanol): 271 mµ (# = 16830) 260 mµ (# = 18667) f) Diimide reduction to 3- (4'-dioxybenzene-1'-2'-cyclohexyl) -4- (3'-ethylenedioxy) -hexene-3 (VI) To a solution of 9.13 g of diyne (V) in 480 cc of benzene and 240 cc of methanol 300 g of dry potassium salt of azodicarboxylic acid are added and very slowly added dropwise a mixture of 97.2 cc of glacial acetic acid, 194.4 cc of methanol at room temperature with stirring and 194 ccm of benzene (drop sequence approx. 8-10 sec.). The decolorized solution is with Soda solution neutralized and worked up with benzene in the usual way. Man receives 9.28 g of brown, oily crude product, which is determined by preparative thin-layer chromatography (Cyclohexane / ethyl acetate 5: 1) is purified by running twice.

6.70 g (72%) of pale yellow Cil are obtained.

IR: (as an oil film) 6.14 µ (1629 / cm) # C = C double bond bands 6.23 µ (1605 / cm) # 8.07 µ (1239 / cm) Arylketalbande 9.37 P (1067 / cm) Ethylketalbande g) Arylketal cleavage by Birch-Beduction with subsequent acidic enol ether cleavage and ethylene spiritual cleavage to a mixture of 3- (4'-oxo-cyclohexyl) -4- (3'-hydroxy-cyclohexyl) -hexene-3 and dione I and subsequent oxidation 500 mg of en-diketal VI are in 15 ml of abs. Tetrahydrofuran and 5 ml of abs. Ethanol dissolved and liquid to 1.7 g of lithium in 100 ml within 5 minutes. Ammonia dripped. After 2 hours, it is decomposed with aq. Methanol, allows the ammonia to evaporate and, after adding saturated ammonium chloride solution, works up with benzene in the usual way. The isolated oil is heated under reflux for 30 minutes in a mixture of 6o nil acetone and 36 ml in sulfuric acid, the solvent is distilled off after neutralization with dicarbonate ii vacuum and worked up with benzene in the usual way. 373 mg of crude oil are obtained. By thin-layer chromatography (cyclohexane-ethyl acetate 1: 1) it can be seen that a mixture of keto alcohol and dione is obtained. Without further purification, the crude oil is used in a Sarett oxidation. to do this, it is dissolved in 20 ml of abs. Pyridine and it is added dropwise to a solution of 1 g of chromium trioxide in 30 ml of abs. Pyridine. After standing overnight, the reaction mixture is filtered through 30 g of aluminum oxide (activity level 2) with ethyl acetate. 297 mg of 2,88% oily product are obtained, which crystallizes when sprayed with ether. M.p. 96-980 IR 5.85 µ (1709 / cm)

Claims (1)

Process for the preparation of 3- (4'-oxocyclohexyl) -4- (3 '-oxo-cyclohexyl) -hexene-3 of the formula 1 characterized in that one cyclohexane-carboxylic acid ethyl ester of the general formula II and IIa in which R1 and R2 always have the same meaning and either two hydrogen atoms or two methyl groups and R3 are a lower alkyl radical, are subjected to a mixed acyloin condensation with one another in the presence of alkali metals, the reaction mixture obtained is oxidized and the diketone mixture obtained in this way is the unsymmetrical compound of general formula III *) and separates an open or ring-shaped ketal grouping from monovalent or bivalent aliphatic alkonols, then reacts it with lithium acetylide or acetylene magnesium halides, the resulting llexadiyne compound of the formula IV with diphosphorus tetraiodide in the presence of carbon disulfide and tertiary organic bases, the compound of formula V obtained with L) iimide to form the ilexene compound of the formula VI reduced and the compound of formula VI thus obtained is reduced with alkali metals in ammonia or primary aliphatic amines in the presence of alcohol, then treated with acid and oxidized.