DE1297602B - Process for the production of delta 4, 6-3-oxo-6-chloro-19-nor-steroids - Google Patents

Description

I 2

The invention relates to a new method Am. Chem. Soc, 80, pp. 3161 to 3163 (1958)]. In the case of the previous process for the preparation of zl ^{4> e} -3-oxo-6-chloro-19-nor-steroidal processes, however, it is surprising that they are identical. These compounds have valuable pharmacological properties that carry out this reaction on a hydroxyl group: for example, the Zl ⁴ ' ⁶ - leaves, which has a halogen atom in the vicinal position, are 3 - oxo - 6 - chloro - 11 β - hydroxy - 17α - ethinyl -19 - normally 5 androstadien since in the alkaline treatment of the suif onsäureesters and Zl ^{4 'e} -3,20-dioxo-6-chloro-17a with the reformation of the epoxide or the formation of acetoxy-19-nor-pregnadiene because their strong pro- a 7 (8) double bond was to be expected. gestativen effect and Zl ^{4 'e} -3-oxo-6-chloro-17 / J is also surprising that the formation of a 7 "-Sulhydroxy-17" -methyl-androstadien because of its pre-f onsäureesters proceeds more easily, since the 7a-hydropartic ratio of androgenic to anabolic ioxyl group is axially located and on the other hand it is known to be effective. is that z. B. in the case of the axial 11 / J-hydroxyl group

Although there are a number of processes for the production of esters, which cannot be readily produced, 6-halo-Zl * ' ^e -3-keto-steroids with angu- [cf. Journ. At the. Chem. Soc. 80 (1958), loc. Cit.]. Larger C-19 methyl group known. So you can z. B. As starting materials for the inventive method

6-Halogen-Zl ⁴ -3-ketones with dehydrating agents, 15 can drive in particular zJ ⁴ -3-Oxo-6a, 7 «-oxidoz. B. with chloranil, or Zl behändem ^{4 'e} -3-ketone compounds androstan-19-nor-of and 19-nor-prezuerst with a peracid to / J ⁴ -6,7-oxido-3-ketones gnanreihe be used z. B. zI ⁴ -3-Oxo-6 ", 7aoxidieren [cf. Chem. Reports, Vol. 94 (1961), p. 1225 oxido-17/3-hydroxy-androstane, Δ ⁴ -3-Oxo-6 ", 7" -oxidobis 1240, German Auslegeschrift 1075114, USA. methyl-, -17a-ethyl-, -17'-allyl-, -17a-ethinyl-, patent 2 968 662] and treat these with a halogen-na-vinyl-n / S-hydroxy-androstene and, in particular, hydrochloric acid [Journ. At the. Chem. Soc, their 17-esters, e.g. B. Acetate, Propionate, Butyrate, 82 (1960), pp. 1230 to 1235], in which case the phenyl propionates, capronates, decanoates, undecy-J ⁴ ' ⁶ -6-halo-3-ketones are formed directly. These verlenates or benzoates, J ⁴ -3,20-dioxo-6 ", 7" -oxido drive can now not or only very poorly on pregnen, Zl ⁴ -3,20-dioxo-6a, 7 "-oxido 17 «-hydroxy-, 19-nor-steroids transferred. With Dehydrierungsmit- 25 -Ha-acetoxy-, -Ha-capronyloxy-pregnen, Δ ^ 3.20-Diteln, z. B. with chloranil, aroma oxo-oaJa-oxido-U / JjlTa-dihydroxy ^ l-acyloxy-pretization of the ring A takes place. The acid treatment of gnene, il ⁴ -3,20-dioxo-6 ", 7a-oxido-ll _J 5,17" -dihydroxy-6,7-oxido compounds, on the other hand, leads to the loa-methyWl-acyloxy-pregnene, / I ⁴ -3,20-Dioxo-6a, 7a-19-Nor-steroids, also especially with chloro-oxido-ll & na-dihydroxy-loa ^ l-diacyloxy-pregnene, hydroic acid in glacial acetic acid, to inconsistent Pro- 30 zJ ⁴ - 3,20-Dioxo-6a, 7 (X-oxido-9 <x-fluoro-ll ^ ₅ 17iX-dihyducts: Thus, according to the last example, one obtains the droxy-loa-methyl ^ l-acyloxy-pregnene, Zl ⁴ - 3,20-Dioxo mentioned work in Journ. Am. Chem. Soc, 82 (1960), 6a, 7 "-oxido-9" .- üuor-llji?, 17 "-dihydroxy-16ix, 21-di-p. 1235 from 250 mg of the 6 ", 7" epoxide of 19-noracyloxy-pregene.

17a-äthinyl-testosterone in the case of treatment with chlorine- Particularly suitable starting materials are, however, the following

hydrogen in glacial acetic acid 150 mg of a mixture containing 35 gende 19-nor-compounds: Zl ⁴ -3-oxo-6a, 7a-oxide by chromatographic purification about 100 mg of the 17/3-hydroxy-19-nor-androsten and its 17 / 3-esters, J ^{4 'e} -17 "-Äthinyl-19-nor-testosterone yields (40% of ⁴ J -3-oxo-6a, 7a-oxido-17a-methyl-17/3-hydroxy-19-used Starting material), which, however, according to Schmelz- nor-androsten and especially its esters, Δ ⁴ -3-Οχο -punkt still seems to be impure. In the presence 6a, 7a-oxido-17a-allyl-17/3-hydroxy-19-nor-androsten means a free or esterified tertiary 17-hydroxy-40 and especially its ester, / d ⁴ -3-oxo-6 « , 7a-oxido group can also aromatize the ring B 17a-äthinyl-17 ^ -hydroxy-19-nor-androstene and its take place, with splitting off of the 17-hydroxy ester, zl ⁴ -3,20-dioxo-6 « , 7a-oxido-19-nor-pregnen or acyloxy group and migration of the 18-methyl-Zl * -3,20-dioxo-6a, 7a-oxido-17a-hydroxy-19-nor group2d ⁵ < ¹⁰ >' ^e ' ⁸ ( ⁹ >' ¹³ < ¹⁴ > tetraenes are formed, and the pregnene, Zl ⁴ -3,20-dioxo-6 ", 7a-oxido-17a-acetoxy yield drops even lower. 45 19-nor-pregnen , Zl ⁴ -3,20-dioxo-6 ", 7a-oxido-17" -

There has now been a new process for the production of capronyloxy-19-nor-pregnen.

of Δ ⁴ ' ⁶ -3-oxo-6-chloro-19-nor-steroids found, according to the process, the Zl ⁴ -3-oxo-6 «, 7« -oxido better yields and in the strongly acidic 19-nor- steroids treated with hydrochloric acid, reaction conditions are avoided and that is why this treatment is carried out under mild semi-straight conditions for compounds of the 19-norsteroid series, 50 under which the resulting which are sensitive to strong acids, J ⁴ -3 -Oxo-6ß-chloro-7a-hydroxy-steroids are resistant, is particularly advantageous. as well as at low temperatures, e.g. B. between

The new method consists in that a -20 and + 30 ⁰ C, and in weakly basic solution-J ⁴ -3-Oxo-6 ", 7" -oxido-19-nor-steroid averages for some time, especially in Ethers such as diethyl ether, hydrochloric acid under mild conditions in diisopropyl ether, ethyl butyl ether, tetrahydrofuran, a weakly basic solvent in the case of lower dioxane, glycol dimethyl ether, polyglycol dimethyl temperature, especially at room temperature, ether, or similar solvents , on the obtained 6 /? - chloro-7a-hydroxy-Ver. The solvents mentioned can optionally

bond an organic sulfonic acid derivative as sul- with other solvents such as hydrocarbons fonylating agent in a manner known per se, mono- or halogenated hydrocarbons, diluted Can act and the 6/9-chloro-7 «-sulfonyloxy- are formed. Treatment with the hydrogen chloride compound with a basic agent in itself acidic harm in anhydrous or water-containing treated in a familiar way. Medium, but is as far as possible

The transfer of a hydroxyl group, e.g. B. an exclusion of water is often advantageous. lloc-hydroxyl group, of a steroid into a sulfone 65 For the process according to the conversion of the 7-hyacid ester group and the cleavage of the sulfonyloxy group into a sulfonyloxy group is used reactive derivatives of aliphatic or aro are already known to form a double bond [see. German Auslegeschrift 1 004 610, Journ. matic sulfonic acids, especially their halides,

ζ. B. Methanesulfonäurechlorid, ethanesulfonic acid chloride, p-toluenesulfonic acid chloride or p-bromobenzenesulfonic acid bromide. The esterification is carried out in the presence of a tertiary base, e.g. B. pyridine, optionally with the addition of an inert solvent such as benzene, methylene chloride or dioxane.

The cleavage of the 7-sulfonyloxy group with the formation of a 6, (7) double bond takes place under the action of basic agents, e.g. B. with tertiary bases such as pyridine, collidine, dimethylaniline, optionally with the addition of an inert diluent. It is particularly advantageous to use dimethylformamide, diethylformamide, dimethylacetamide alone or with the addition of lithium halides, such as lithium chloride, lithium bromide, or in particular with the addition of alkali or alkaline earth metal carbonates, such as lithium carbonate, calcium carbonate, strontium carbonate or alkali metal acylates such as sodium acetate or potassium acetate. The cleavage is carried out at elevated temperature, advantageously between 50 and 15O ⁰ C, performed.

The procedure is described in the following examples. The temperatures are in degrees Celsius specified.

example 1

A solution of 9.25 g of A ⁴ -3-oxo-6a, 7 "-oxido-17" - methyl-17 ^ -acetoxy-19-nor-androstene in 450 ml of 1N hydrochloric acid in dioxane is left to stand for 30 minutes at room temperature and then poured onto 3 l of a 2.5 percent sodium hydrogen carbonate solution. After shaking out three times with methylene chloride, the organic solutions are washed once with water, dried and evaporated in vacuo. The last residues of dioxane are removed in a high vacuum. The crude Zl ⁴ -3-oxo-6'-chloro-7 /? - hydroxy-17oc-methyl-17 ^ -acetoxy-19-nor-androstene is dissolved in 100 ml of pyridine and stirred and cooled with ice Table salt mixture mixed with 10 ml of methanesulphonic acid chloride. After standing at 64stündigem -1O ⁰ C is poured with stirring to dilute sodium bicarbonate solution, extracted five minutes later with methylene chloride and washed with saturated sodium bicarbonate and water. The crude Δ ⁴ -3-oxo-6 _J 8-chloro-7a-mesyloxy-17'-methyl-17je-acetoxy-19-or-androsten obtained after drying and evaporation of the organic solution at 30 ° in vacuo and dried in a high vacuum is heated with 600 ml of dimethylformamide and 100 g of dry sodium acetate for 1 hour with stirring in a stream of nitrogen to 80 ° and then left to stand for 60 hours at room temperature. After adding water and shaking three times with methylene chloride, the organic solutions are washed with water, dried and evaporated first in a water-jet vacuum and then in a high vacuum. The crystalline, yellow-colored residue, dissolved in benzene, is filtered through 500 g of aluminum oxide (activity II), washing with benzene. After evaporation of the eluate in vacuo and recrystallising the residue from a methylene chloride-ether mixture is obtained 7.18 g zl ⁴ - ⁶ -3-oxo-6-chloro-17a-methyl-17 /? - acetoxy-19-nor- androstadien from 207 to 209 ° F. (dec.).

The ζΙ ⁴ -3-Οχο-6λ, 7 "-oxido-17" -methyl-17 / S-acetoxy-19-nor-androstene used as starting material is prepared as follows: 60 g / 1 ⁴ -3-Oxo-17ix -methyl-17/3-acetoxy-19-nor-androstene are dissolved in 11% dioxane and 120 ml of ethyl orthoformate, and a solution of 3 g of p-toluenesulfonic acid in 480 ml of dioxane is added. After 2 _^3/4 hours of standing at room temperature and addition of 50 ml of pyridine until the onset of crystallization is evaporated, mixed with benzene and washed twice with water in vacuo. The aqueous solutions are extracted once more with benzene. The residue of the dried benzene solutions evaporated in vacuo is dissolved in xylene, whereupon it is evaporated again in vacuo and this operation is repeated twice. The crude Δ ^{3> 5} -3-ethoxy-17a-methyl-17 _/ S-acetoxy-19-nor-androstadiene obtained in this way is dissolved in 2.41 acetone, while stirring, with a solution of 45 g of sodium acetate in 300 ml of water and then 66 g of bromosuccinimide and 51 ml of glacial acetic acid are added. After stirring for 3 hours with ice cooling, a solution of 60 g of potassium iodide in 200 ml of water and then a solution of 120 g of Na-

ao trium thiosulfate in 250 ml of water. Thereon the acetone is evaporated off in vacuo and the residue extracted three times with methylene chloride. The organic solutions are washed with sodium hydrogen carbonate solution and water and dried

»5 and evaporated in vacuo. The crude ⁴ -3-oxo-6-bromo-17 "-methyl-17jÖ-acetoxy-19-nor-androstene is mixed with 750 ml of dimethylformamide and 50 g of calcium carbonate and allowed to boil for 45 minutes with stirring in a stream of nitrogen. After cooling, filtering off and washing with 11% alcohol, the filtrate mixed with a solution of 20 g of sodium acetate in 15 ml of water is evaporated in vacuo. The residue is mixed with xylene, filtered again and washed with xylene. After evaporation in vacuo, the mixture is dissolved in benzene, evaporated again in vacuo and the residue is chromatographed on 2 kg of aluminum oxide (activity II). From the crystalline fractions eluted with benzene-petroleum ether (4: 1) mixture and the first with benzene-petroleum ether (1: 1) mixture, 14.4 g of ⁴ -3-oxo-17a are obtained after redissolving from petroleum ether -methyl-17) S-acetoxy-19-nor-androstene from m.p. 94 to 95 °. The later fractions eluted with benzene-petroleum ether (1: 1) mixture and the fractions eluted with pure benzene contain the Zl ⁴ - ^e -3-Oxo-17 «-methyl-17 ^ -acetoxy-19 _: nor-androstadiene, of which, after dissolving from an ether-petroleum ether mixture, 21.5 g with a melting point of 183.5 ° to 185.5 ° are obtained. Further dissolving increases the m.p. to 188.5 to 189.5 °. UV spectrum (solvent: fine spirit) : ε 283 πιμ = 26,200; [x] f = -17 ° (c = 1.024 in chloroform).

IR spectrum (solvent: methylene chloride): 5.77μ (acetate); 6.00 μ + μ + 6.16 6.29 μ (zl ⁴ - ⁶ -3-ketone) and 8.10 μ (acetate).

To a solution, cooled to 5 ° solution of 20.6 g · J ^{4 6} -3-oxo-17 "-methyl-17/3-acetoxy-19-nor-androstadien in 2 1 of methylene chloride is to _# 400 rnl of a l, 56n Solution of phthalmonoperic acid in ether, left to stand for 21 hours at room temperature and then 800 ml of 2N soda solution pour in while cooling with ice and stirring. 15 minutes later, it is rinsed with methylene chloride in a separating funnel and successively with 500 ml of 2N soda solution, with a solution of 60 g of potassium iodide and 3 ml of glacial acetic acid in 600 ml of water, then without separating with a solution of 60 g of sodium thiosulfate in water and then Shaken twice more with 500 ml of 2N soda solution each time and twice with dilute sodium chloride solution. The aqueous solutions are washed twice with methyl

Lene chloride extracted, whereupon the organic solutions are dried and evaporated in vacuo. Of the The residue is dissolved in benzene and washed with 10 g of aluminum oxide (activity II) Benzene filtered. After evaporation and redissolution of the residue from a methylene chloride-ether mixture using 1 g of Carboraffin, 9.4 g of zH-S-Oxo-öaJa-oxido- ^ a-methyl-n ^ -acetoxy-19-norandrosten are obtained, which melts at 168 to 169 ° after further dissolving. By chromatography the first Mother liquor in 300 g of aluminum oxide (activity II) are a further 260 mg of the above-described oxide compound obtain. [x] f? = + 26 ° (c = 0.918 in chloroform). UV spectrum (solvent; fine spirits): ε 241 ηιμ. = 15 300. IR spectrum (solvent: methylene chloride): 5.77μ + 8.09μ (acetate) and 5.94μ + 6.14μ (Ζΐ * -3-Κ6ίοη).

Example 2

(For comparison with an unclaimed method under more vigorous conditions).

A solution of 100 mg of Zl ⁴ -3-oxo-6 ", 7" -oxido-17a-methyl-17 /? - acetoxy-19-nor-androstene in 5 ml of 1N hydrochloric acid in dioxane is left to stand for 75 hours at room temperature, whereupon poured onto dilute sodium hydrogen carbonate solution and extracted twice with methylene chloride. The residue of the solutions washed with water, dried and evaporated in vacuo is chromatographed on 3 g of aluminum oxide (activity II). By redissolving the crystalline fractions eluted with benzene from a methylene chloride-ether mixture, only 25 mg of Δ * ' ⁶ -3-oxo-6-chloro-17 «-methyl-17JS-acetoxy-19-norandrostadiene with a melting point of 209 bis 211 ° (decomp.), Which after redissolving gives 21 mg of a product melting at 225 to 226.5 ° (decomp.). UV spectrum (solvent: fine spirit): ε 284 πιμ = 22 800. IR spectrum (solvent: methylene chloride): bands among others at 5.77 μ (acetate); 5.98 µ + 6.21 µ + 6.29 µ (Zl ⁴ ' ⁶ -3-ketone) and 8.12 µ (acetate).

Example 3

250 mg / J ⁴ -3,20-Dioxo-6 «, 7oc-oxido-17a-acetoxy-19-nor-pregnen are dissolved in 15 ml of 1N hydrochloric acid in dioxane and left to stand for ¹ J for ₂ hours at 25 °. The solution is then poured onto water and neutralized with sodium hydrogen carbonate solution. The precipitated crude product is taken up in ether-methylene chloride (5: 1) mixture, washed neutral with water, the solution is dried and evaporated in vacuo. The raw ■ d

Droxy-17öc-acetoxy-19-nor-pregnen is dissolved directly in 3 ml of pyridine without purification, 0.3 ml of methanesulfonic acid chloride is added at -5 to 0 ° while stirring and left to stand for 2 days at -10 °. The reaction product is poured onto dilute sodium hydrogen carbonate solution, taken up in ether, the ethereal solution washed neutral, dried and evaporated in vacuo. The resulting Zl ⁴ -3,20-dioxo-o / S-chloro ^ a-mesyloxy-na-acetoxy-W-nor-pregnen is dissolved in 25 ml of dimethylformamide and, after addition of 4.5 g of anhydrous sodium acetate, heated for 75 minutes with stirring in a stream of nitrogen to 85 °. The cooled reaction mixture is diluted with water, extracted with ether-methylene chloride (5: 1) mixture, the organic layer is washed 5 times with 100 ml of water each time, dried and evaporated. The crude product obtained is dissolved in benzene and chromatographed on 15 times the amount of aluminum oxide (activity II). With the same solvent, 105 mg of pure Zl ⁴ ' ^e -3,20-dioxo-6-chloro-17aacetoxy-19-nor-pregnen are eluted, which is recrystallized from methylene chloride-hexane. Among other things, absorption bands at 5.78 μ, 5.85 μ, 6.02 μ, 6.22 μ, 6.31 μ and 8.10 μ appear in the IR spectrum of the compound. UV absorption maximum at 284 πιμ (ε = 24 100).

Claims (4)

Patent claims: 1. A process for the preparation of Λ ⁴ · ⁶ -3-Οχο-6-chloro-19-nor-steroids, characterized in that a Zl ⁴ -3-oxo-6a, 7a-oxido-19-nor-steroid some Time treated with hydrochloric acid under mild conditions in a weakly basic solvent at low temperature, especially at room temperature, an organic sulfonic acid derivative is allowed to act on the 6/3-chloro-7-hydroxy compound obtained as a sulfonylating agent in a manner known per se and the o ^ -Chlor ^ w-sulfonyloxy compound treated with a basic agent in a manner known per se. 2. The method according to claim 1, characterized in that ^ l ⁴ -3-oxo-6a, 7a-oxido-19-norandrostene or -pregnene used as starting materials. 3. The method according to claim 1, characterized in that the treatment of the starting steroid with hydrochloric acid in an ether. 4. The method according to claim 1, characterized in that a dialkylformamide is used as the basic agent and an alkali metal acetate is used.