Process for the preparation of intermediates used in the synthesis of progesterone antagonists (synthesis of onapristone).

The present invention relates to a new process for the preparation of intermediates of the general formula III<chemistry id="chem0001" num="0001"><img file="EP0447014A2_D0001.tif" /></chemistry>wherein<ul id="ul0001" list-style="none"><li>R '<chemistry id="chem0002" num="0002"><img file="EP0447014A2_D0002.tif" /></chemistry>with R 'and R "in the meaning of hydrogen or alkyl having 1 to 4 carbon atoms or R' and R" with inclusion of N in the meaning of a saturated 5- or 6-membered ring, wherein in the ring besides N there is another heteroatom such as 0, N, S can be present, as well as the corresponding tertiary N-oxides and the acid addition salts,</li><li>-OR "'with R' '' meaning methyl, ethyl, propyl, methoxyphenyl, allyl or β-dimethylaminoethyl, R² a hydrogen atom, a methyl or ethyl group, and</li><li>Z represents an ethylene or 2,2-dimethylpropylene group.</li><li>The compounds (intermediates) of the general formula III are known.</li><li>These intermediates are required for the preparation of antigestagens (competitive progesterone antagonists) of the general formula I<chemistry id="chem0003" num="0003"><img file="EP0447014A2_D0003.tif" /></chemistry>wherein<ul id="ul0002" list-style="none"><li>R 'and R² have the meaning given in formula III and</li><li>R³ - (CH₂)_n-CH₃ with n = 0-4, - (CH₂)_n-CH₂-O (S) R^IV with n = 0-4 and R^IV in the meaning of hydrogen or alkyl having 1 to 4 carbon atoms, -CH = CH- (CH₂)_nOR^v with n = 1-4 and R^v in the meaning of hydrogen, alkyl or alkanoyl each having 1 to 4 carbon atoms, -C = CX with X in the meaning of hydrogen, alkyl having 1 to 4 carbon atoms or halogen, - (CH₂)_nCH₂CN with n = 0-3 or<chemistry id="chem0004" num="0004"><img file="EP0447014A2_D0004.tif" /></chemistry>with Y meaning hydrogen or OR^v with R^v in the meaning given above,</li><li>R⁴ Hydroxy, alkyloxy or alkanoyloxy each having 1 to 4 carbon atoms or<chemistry id="chem0005" num="0005"><img file="EP0447014A2_D0005.tif" /></chemistry>R³/ R⁴ where R³ in α position and R⁴ in the β position or R³ in β position and R⁴ stand in the α-position to the steroid structure.</li></ul></li></ul>

These antigestagens of the formula I and a process for their preparation are described in European Patent 0129 499. The 11β- (4-dimethylaminophenyl) -17β-hydroxy-17β- (3-hydroxypropyl) -13a-methyl-4, 9-gonadien-3-one (onapristone) has so far proven to be particularly advantageous (Schneider et al., Eur. J. Cancer Clin. Oncol., 25, pp. 691-701 (1989). Areas of indication include tumor therapy (breast cancer), use in induction of labor and the treatment of endometriosis.

Another process for the preparation of intermediates of general formula II<chemistry id="chem0006" num="0006"><img file="EP0447014A2_D0006.tif" /></chemistry>wherein<ul id="ul0003" list-style="none"><li>Z and R²have the meaning given in formula III,</li><li>emerges from European patent application 0259 248. Both known methods are based on the connection<chemistry id="chem0007" num="0007"><img file="EP0447014A2_D0007.tif" /></chemistry></li><li>wherein Z has the meaning given in formula III.</li><li>The compound of formula III can be prepared, for example, by the process described in EP-A 0298020.</li></ul>

In Figure 1, the two known processes for the preparation of antigestagens of the formula I are compared with each other using the example of the synthesis of onapristone; THP stands for the 2-tetrahydropyranyl residue.

The reaction sequence ⑤ → ⑥ → ⑦ → ⑧ → ⑨ is described in European Patent 0 129 499, the sequence ⑤ → ⑬ → ⑭ → ⑮ → ⑨ in EP-A 0 259 248.

In the process according to the invention for the preparation of the intermediates of the general formula III, a compound of the general formula II is now used with a compound of the formula<chemistry id="chem0008" num="0008"><img file="EP0447014A2_D0008.tif" /></chemistry>(Hal = halogen) with the addition of a Cu (I) salt, such as CuCI, Cul or CuCN, implemented.<chemistry id="chem0009" num="0009"><img file="EP0447014A2_D0009.tif" /></chemistry>

The compound thus obtained is then processed further to give an end product of the general formula I in the manner given in EP 0129 499. (in Fig. 1 ⑧ → ⑨ → ⑩ → ⑪).

The successful course of the addition of the nucleophilic reagent exclusively to the epoxy function of the compound of the general formula II is surprising. The nucleophilic attack on the 17-keto function should have been expected.

The method according to the invention offers decisive advantages over the known methods. With nucleophilic epoxy opening ⑮ → ⑨ according to EP-A 0259 248, a yield of 84.3% can be achieved; however, it has been found that ⑮ (and its hydrogenation product) has a considerable tendency to decompose and is therefore not stable in storage. This has a particularly negative impact on the implementation of technical approaches, if an intermediate storage of large quantities is required.

The overall yield can be increased if unreacted material of the formula 13 is recovered after the irradiation to isomerize the 13β-methyl or ethyl group and is used again for the renewed irradiation. The recovery is described in the example "Production of the starting product".

When producing @ via the reaction sequence described in EP-A 0129 499, the oxidation of the 17β-hydroxy to the 17-keto group (⑥ → ⑦) can only be carried out under the conditions of an Oppenauer oxidation, so that co-oxidation of the dimethylamino function is prevented becomes. Since the Oppenauer oxidation is a typical equilibrium reaction, the Steroids 44 (1989), S. 368 stated yield of 80.5% achieved only by adding an excess of keto component (cyclohexanone in boiling toluene); the keto component causes the equilibrium to shift to the side of the desired 17-keto oxidation product. These drastic, basic reaction conditions lead to condensation reactions of the added keto component (aldol addition, Knoevenagel reaction). The by-products resulting from this in a considerable amount must then be separated off again by washing, filtering and chromatographing. If one wanted to achieve an almost quantitative yield, this would only be possible, if at all, by accepting even larger amounts of by-products that are difficult to separate. Additional difficulties arise because of the easy hydrolyzability of the oxidizing agent aluminum triisopropylate to be used.

It has been found that the oxidation can advantageously be carried out using sulfur trioxide / pyridine, as specified in regulation I). A yield of about 85% is then also "only" achieved, but pure 17-ketone @ is obtained without - on a technical scale very complex - chromatography.

The new process thus advantageously leads to the compound ⑧ (→ ⑨) or bypassing the decomposable compound ⑮ via ⑧ to ⑨ bypassing the expensive Oppenauer oxidation which limits the yield.

The following examples serve to explain the invention in more detail.

Manufacture of the starting product

I) 5α, 10α-epoxy-3,3- (2,2-dimethyltrimethylenedioxy) -9 (11) -estren-17-one

Oxidation of ⑤ with sulfur trioxide / pyridine

A suspension of 32.6 g (0.20 mol) of sulfur trioxide-pyridine complex in 25 ml of anhydrous dimethyl sulfoxide is cooled to 10 ° C. and under protective gas within 30 minutes with 30.2 g (0.83 mol) of N-ethyl -diisopropylamine added. A weak exotherm of 3-5 C is observed. A solution of 24.8 g (66.2 mmol) of 3,3- (2,2-dimethyltrimethylene dioxy) -5 «, 10α-epoxy-9 (10) estren-17ß-oi in 50 ml of anhydrous dimethyl sulfoxide is then added within Dropped 10 minutes in such a way that the temperature of the reaction mixture does not exceed 25 C. Then it is stirred for one hour at room temperature. After checking the thin layer chromatography for complete conversion (silica gel₆₀-Finished panels / Merck; n-hexane / ethyl acetate = 1/1) 100 ml of ethyl acetate are added. The reaction mixture is then cooled to 10 ° C. and 100 ml of ice-cold water are carefully added within 15 minutes, so that the temperature does not rise above 20 ° C. After stirring for 15 minutes, the phases are separated. The water phase is extracted with 100 ml of ethyl acetate. The combined ethyl acetate phases are washed twice with 50 ml of water each time, dried over 25 g of sodium sulfate and filtered. The filtered ethyl acetate solution is co-distilled with the successive addition of n-hexane until a boiling point of 68 ° C. (pure n-hexane) is reached. The mixture is then cooled to 0 ° C. and stirred for a further 15 minutes. The colorless precipitate formed is filtered off with suction and dried to constant weight. The crude product thus obtained (27.6 g; yield&gt; theory) is purified by heating with 55 ml of n-hexane. 20.98 g (85.1%) of the title compound with a melting point of 125-127 ° C. are obtained.

II) 5a, 10α-epoxy-3,3- (2,2-dimethyltrimethylenedioxy) -13α-methyl-9 (11) -gon-17-one

25th g 5a, 10α-epoxy-3,3- (2,2-dimethyltrimethylenedioxy) -9 (11) -estren-17-one are dissolved under protective gas in 6 l of hexane for 3.5 hours at room temperature with a high pressure Hg lamp (Heraeus , TQ 150, 150 W) irradiated in a quartz glass immersion apparatus. After removal of the solvent in vacuo, the residue is chromatographed on aluminum oxide (neutral, stage III) with a mixture of ethyl acetate and hexane. 10.75 g of 5α, 10α-epoxy-3,3- (2,2-dimethyltrimethylene-dioxy) -13α-methyl-9 (11) -gon-17-one and 8 g of starting material are isolated as white foams. 10.75 g = 43% (63% based on converted starting material).

example

11β- (4-dimethylaminophenyl) -3,3- (2,2-dimethyltrimethylene dioxy) -5α-hydroxy-13A-methyl-9-gonen-17-one

2.63 g of magnesium shavings are placed at room temperature under protective gas in 20 ml of absolute tetrahydrofuran and first mixed with 0.3 ml of 1,2-dibromoethane. After activation of the magnesium, 21.5 g of 4-bromo-N, N-dimethylaniline dissolved in 200 ml of absolute tetrahydrofuran are added dropwise so that the internal temperature in the reaction vessel does not exceed 40.degree. increases. After formation of the aryl magnesium compound, the reaction mixture is cooled to -10 ° C., 270 mg of copper (I) chloride are added, and a solution of 5 g of 5α, 10α-epoxy-3,3- (2,2-dimethyltrimethylenedioxy) 13α -methyl-9 (11) -gon-17-one slowly added dropwise in 70 ml of absolute tetrahydrofuran. After four and a half hours of stirring at -10 ° to 0 ° C, the reaction mixture is poured onto saturated ammonium chloride solution and the aqueous phase extracted several times with ethyl acetate. The combined organic phases are washed neutral with saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The residue is chromatographed on silica gel with a mixture of ethyl acetate / hexane. 6.42 g of 11β- (4-dimethylaminophenyl) -3,3- (2,2-dimethyltrimethylenedioxy) -5α-hydroxy-13α-methyl-9-gonen-17- one are obtained as a white foam. 6.42 g = 96.9%.