DE1180366B - Process for the preparation of 16ª ‡ -alkyl steroids of the pregnane series - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

GERMAN

PATENT OFFICE

EDITORIAL

Boarding school Class: C 07 c

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German class: 12 ο -25/05

C19900IVb / 12o October 2, 1959 October 29, 1964

The invention relates to a new, productive process for the preparation of 16a-alkyl steroids the Pregnan series.

It is known that J ¹⁶ -20-ketones of the pregnane series can be converted into 16α-alkyl-20-keto-pregnanes by reaction with alkyl magnesium halides in the presence of copper (I) halides. According to the information for this reaction described in the literature, however, no satisfactory yields are obtained. When this reaction is transferred to the zJ ¹⁶ -3 /? - hydroxy-20-keto-allopregnene or its esters, for example, the yield of 16a-alkyl compound is no more than about 20%.

It has now been found that zl ¹⁸ -20-Ketopregnenverbindungen can be converted by treatment with alkylmagnesium halides in the presence of copper (I) halides in high yield into the corresponding 16a-Alkylsteroide the pregnane series, if the reaction with the alkyl magnesium halide and the copper (l) halide in the presence of tetrahydrofuran and in the absence of alkyl halide, the 20-metal enolates formed are decomposed with hydrolyzing or acylating agents and any 3- or 3- and 21-position hydroxyl groups present in the compounds thus obtained are known Esterified way.

The process according to the invention is shown, for example, in the following reaction scheme:

CuCl

Tetrahydrofuran

AcO Process for the production of 16a-alkyl steroids of the pregnane series

Applicant:

CIBA Aktiengesellschaft, Basel (Switzerland) Representative:

Dipl.-Ing. E. Splanemann, patent attorney, Hamburg 36, Neuer Wall 10

Named as inventor:

Dr. Albert Wettstein,

Dr. Karl Heusler,

Dr. Jindrich Kebrle, Basel, Dr. Charles Meystre, Ariesheim, Dr. Peter Wieland, Basel (Switzerland)

Claimed priority:

Switzerland of October 10, 1958 (64 888), of November 28, 1958 (66 695), of September 16, 1959 (78 292)

CH ₃
C-OMgJ

- CH ₃

HO

CH ₃ CO

^L - CH ₃

dilute acid

^L - CH ₃

AcO

409 709-341

Lower alkyl magnesium halides are primarily used as alkyl magnesium compounds, ζ. B. methyl magnesium iodide. When carrying out the process according to the implementation, care must be taken that no more alkyl halide is present in the alkylmagnesium halide solution used. B. benzene, or can be achieved by using an excess of magnesium. The compounds customary for this reaction, in particular copper chloride, are used as copper (I) halides. Under these reaction conditions, ester groups (ζ. Β. Esterified hydroxyl groups, such as acetoxy groups) are hardly or not at all and other α, β-unsaturated keto groups (e.g. the J ⁴ -3-keto and zl ^ -S-keto groups) only attacked to a minor extent.

The reaction is usually carried out at room temperature. The decomposition of the educated 20-metal enolates are made with either hydrolyzing agents, e.g. B. by decomposition with dilute acids such as hydrochloric acid, sulfuric acid, or with ammonium chloride solution, or with acylating agents; in the latter case, the corresponding acylates are used instead of the free 20-ketones Obtain enols. Obtained 16a-alkyl-20-ketopregnane compounds with free hydroxyl groups in the 3- or 3- and 21-position can, if if desired, converted into corresponding esters in a known manner.

According to the method of the invention, it is possible in J ¹⁶ -20-keto-pregnenen and -allopregnenen in the 16et position an alkyl, in particular a lower alkyl, ζ. B. to introduce the methyl radical in high yield.

Those obtained by hydrolytic decomposition 16a-alkyl compounds can indeed be followed by a known method to the corresponding zl ^{17 <20>} -20-Enolacylate, in particular enol acetates, process, utilized as starting materials for the synthesis of 17a-hydroxy-20-keto-5a - and -5 /? - serve pregnanen. This procedure consists in reacting to the corresponding 20-ketones an acylating agent, e.g. B. acetic anhydride, in the presence of a strongly acidic catalyst, e.g. B. p-toluenesulfonic acid, sulfuric acid or perchloric acid can act. In the case of 20-ketones, which in the 16a position is an alkyl, such as lower alkyl, ζ. B. have a methyl radical, the enol acylation is very difficult because of the presence of this radical, so that the reaction proceeds only slowly and in poor yield even under vigorous reaction conditions.

According to one procedure of the present invention, however, the 20-enol acylates are through direct acylation of the metal enolates formed on exposure to alkyl magnesium halides obtain. The metal enolates are advantageously not isolated, but rather in the reaction solution reacted with acylating agents, in particular with reactive derivatives of carboxylic acids. Such derivatives are especially the anhydrides, halides or quaternary amides of aliphatic, araliphatic, aromatic and heterocyclic carboxylic acids, such as lower fatty acids, z. B. formic acid, acetic acid, propionic acid, butyric acid, phenylacetic acid, p-nitrophenylacetic acid, Benzoic acid, p-methoxy-benzoic acid, 2,4,6-tribromobenzoic acid or furan-2-carboxylic acid. The acylating agents are used in approximately equimolar amounts to the alkyl magnesium halide used. The acylation takes place quickly and is usually complete after a few minutes at room temperature. Occasionally this is to avoid an excessively violent reaction even requires cooling of the reaction mixture. In the acylation usually a mixture of the two enol acylates isomeric in the 20-position is formed. In many cases the mixture or one or both of the forms can be obtained in crystallized form. Both Isomeric forms are obtained in the further processing by peracid oxidation, which is not claimed here and hydrolysis of the 17,20-oxido compounds thereby obtained the same 16a-alkyl-17a-hydroxy-20-ketones.

This embodiment of the process according to the invention not only enables the known 16α-methyl-20-enol acetates to be produced in far better yields than the previously known processes, but also 20-enol acylates which cannot be obtained at all by the known processes can be produced. So it succeeded z. B. has not yet been able to convert 21-acyloxy-20-ketones into 20-enol acylates; likewise it has hitherto been impossible to prepare 20-enol acylates of compounds with free or ketalized / l ⁴ -3-keto grouping without this being changed at the same time. In the case of 11,20-diketones it is possible to achieve a selective enol acylation of the 20-keto group with the previously known processes, but the selective enol acylation of other steroid polyketones was not successful. According to the new process of the present invention, which completely avoids the use of an acidic catalyst, the preparation of 16a-alkyl-20-enol acylates is now possible even in the presence of a 21-acyloxy, e.g. B. acetoxy group, a Δ ⁴ - or / I ^ -S-keto grouping or a ketalized oxo group, z. B. in the 3-, 6-, 7- and / or 12-position.

Suitable starting materials are, for. B. A ¹⁶ -3ß- and 3a-hydroxy-20-keto-5a- and -5 / 3-pregnen, A ¹⁶ -3ß- Hydroxy-ll, 20-diketo-5a-pregnen, zl ¹⁶ -3/3 , lla-dihydroxy-20-keto-5a-pregnen, / l ¹⁶ -3a-hydroxy-l 1,20-diketo - 5ß - pregnen, .d ¹⁶ - 3ß - hydroxy -12,20 - diketo-5a-pregnen, J ^he -3a-hydroxy-12,20-diketo-5 / S-pregnene, / I ⁵ · ¹⁶ - 3ß - hydroxy - 20 - keto - pregnadiene / l ⁵ - ¹⁶ -3 /? - hydroxy-l 1, 20-diketo-pregnadiene, Α ⁵ · ^1β -3β, 11 α-dihydroxy-20-keto-pregnadiene, zl ⁵ · ¹⁶ -3 / 3-hydroxy-12,20-diketo-pregnadiene, / J ⁹ < ⁿ > - ¹⁶ -3 / 3-hydroxy-20-keto-5a-pregnadiene, J ^{9 '11} > - ¹⁶ -3a-hydroxy-20-keto- 5ß - pregnadiene, A ⁴ · ¹⁶ - 3.20 - diketo - pregnadiene, / l ⁵ - ¹⁶ -3-ethylenedioxy-20-keto-pregnadiene, / l ⁵ - ¹⁶ -3-ethylenedioxy - 11α - hydroxy - 20 - keto - pregnadiene, A ^{5 '16} - 3 - ethylenedioxy - 11.20 - diketo - pregnadiene, /11.4,16.3 20-diketo-pregnatrien, -4-9 ( "'-! 6-3.20-diketo-pregnatetraen / 1 ^35-16 -3-ethoxy-20-keto-pregnatrien and the corresponding Compounds in which one or more hydroxyl groups are present ppen are esterified or etherified. Furthermore, the above-mentioned compounds can be used as starting materials, which additionally have a free, esterified or etherified hydroxyl group in the 21-position, ie z. As the / l ^5-16 -3 / 3,21-Dihydroxy-20-keto-pregnadiene, the z! ^5-16 -3-Äthylendioxy-

H-hydroxy-10-keto-pregnadiene, the zl ^{5 '16} -3-ethylenedioxy-21-hydroxy-11,20-diketo-pregnadiene or the /|5, i6.3. Ethylenedioxy-1 la, 21-dihydroxy-20-ketopregnadiene and their esters.

The process products are important intermediate products for the synthesis of corticosteroids with a 16a alkyl radical, e.g. B. of 16a-methyl-9a-fluoro-prednisolone and -prednison, also of 16ct-methyl-17a-hydroxy-progesterone and esters thereof.

The following examples explain the process according to the invention. The temperatures are in Degrees Celsius.

example 1

A Grignard solution of 2 g of magnesium and 7 cm ^{3 of} methyl iodide in 100 cm ^{3 of} absolute ether is mixed with 150 cm ^{3 of} pure tetrahydrofuran. The ether and excess methyl iodide are completely distilled off with a calcium chloride seal. The methyl magnesium iodide suspension obtained in tetrahydrofuran is cooled to 20 ° and the reaction vessel is filled with oxygen-free, dry nitrogen. 400 mg of copper (I) chloride are now added. With stirring and under nitrogen, a solution of 5 g of ¹⁶ -3 ^ -acetoxy-1, 20-diketo-allopregnene in 50 cm ^{3 of} pure tetrahydrofuran is then added dropwise at the same temperature. The solution is stirred for a further 30 minutes, then cooled from the outside with ice and carefully decomposed with an aqueous ammonium chloride solution. The mixture obtained is diluted with ether, the ethereal solution is washed with an ammonium chloride solution, water, a sodium thiosulfate solution and water, dried and evaporated. The amorphous residue is the crude 3 /? - hydroxy-ll, 20-diketo-16a-methyl-allopregnan. It is dissolved in 10 cm ^{3 of} dry pyridine and 20 cm ^{3 of} acetic anhydride and left to stand for 15 hours at 20 °. The solution is then mixed with water, en <. the solution in a vacuum and the residue is taken up in ether. The ethereal solution is washed with dilute hydrochloric acid and water, dried and evaporated. The residue is recrystallized from ether alone, an ether-pentane or ether-isopropyl ether mixture and gives 4.58 g of 3 / S-acetoxy-16a-methyl-ll, 20-diketo-allopregnans. It melts at 142 to 143 °, then crystallizes again into broad prisms that finally melt at 153 °; [α] % = + 80 ° (in chloroform); IR spectrum in methylene chloride: bands at 5.79, 5.86, 7.20 μ (shoulder), 7.26 μ (shoulder), 7.35, 8.13, 9.74 μ, among others.

Example 2

A Grignard solution of 7 g of magnesium and 30 cm ^{3 of} methyl iodide in 200 cm ^{3 of} absolute ether is mixed with 300 cm ^{3 of} pure tetrahydrofuran. The ether and excess methyl iodide are completely distilled off with a calcium chloride seal. The methyl magnesium iodide suspension obtained in tetrahydrofuran is cooled to 20 ° and the reaction vessel is filled with oxygen-free, dry nitrogen. 1 g of copper (l) chloride is now added. With stirring and under nitrogen, a solution of 10 g of ¹⁶ -3 ^, IIIa-diacetoxy-20-keto-allopregnene in 150 cm ^{3 of} tetrahydrofuran is then added dropwise at the same temperature. The solution is then stirred for a further 30 minutes, then cooled from the outside with ice and carefully decomposed with an aqueous ammonium chloride solution. The mixture obtained is diluted with ether, the ethereal solution is washed with an ammonium chloride solution, water, a sodium thiosulfate solution and water, dried and evaporated. The amorphous residue is the crude 3 / 9.1 la-dihydroxy-loa-methyl ^ O-keto-allopregnan. It is dissolved in 40 cm ^{3 of} pyridine and 20 cm ^{3 of} acetic anhydride and left to stand for 15 hours at 20 °. The solution is then mixed with water, concentrated in vacuo and the residue is taken up in ether. The ethereal solution is washed with dilute hydrochloric acid and water, dried and evaporated. The crystalline residue (10.3 g) is recrystallized from methanol, 8.6 g of the 3 / 3.1 la - diacetoxy - 16a - methyl - 20 - keto - allopregnans having a melting point of 172 ° to 174 ° being obtained.

IR spectrum in methylene chloride: bands at 5.79, 5.86, 7.20 μ (shoulder), 7.26 μ, among others (Shoulder); 7.34, 8.13, 8.64, 9.76 µ. A further 0.74 g of the same compound can be obtained from the mother liquors to win.

Example 3

A Grignard solution of 6.9 g of magnesium and 25 cm ^{3 of} methyl iodide in 200 cm ^{3 of} absolute ether is mixed with 200 cm ^{3 of} pure tetrahydrofuran. The ether and excess methyl iodide are completely distilled off with a calcium chloride seal. The methyl magnesium iodide suspension obtained in tetrahydrofuran is cooled to 20 ° and the reaction vessel is filled with oxygen-free, dry nitrogen. 600 mg of copper (I) chloride are now added. ^{A solution of 10 g of 5 '16} -3 /? - acetoxy-20-ketopregnadiene in 100 cm ^{3 of} pure tetrahydrofuran is then added dropwise at the same temperature with stirring and under nitrogen. The solution is stirred for a further 30 minutes, then cooled from the outside with ice and carefully decomposed with an aqueous ammonium chloride solution. The mixture obtained is diluted with ether, the ethereal solution is washed with an ammonium chloride solution, water, a sodium thiosulfate solution and water, dried and evaporated. The residue is recrystallized from acetone, 8.48 g of the zl ⁵ -3, S-hydroxy-16a-methyl-20-ketopregnene being obtained; it melts from 182 °, partially crystallizes again and definitely melts at 188 °.

2 g of this compound are dissolved in 10 cm ^{3 of} pyridine and 20 cm ^{3 of} acetic anhydride in the heat. The solution is left to stand for 15 hours at 20 °, the solution is decomposed with water and evaporated in vacuo. The residue is dissolved in ether, the ethereal solution is washed with dilute hydrochloric acid and water, dried and evaporated. The residue is recrystallized from an acetone-isopropyl ether mixture, 1.9 g of des / I ⁵ -3 /? -Acetoxy-16a-methyl-20-keto-pregnene having a melting point of 182 ° to 184 ° are obtained; [a] 1 ° = 0 ° (chloroform); IR spectrum in methylene chloride: bands at 5.76, 5.86, 7.20 μ (shoulder), 7.27, 7.34, 9.70 μ, among others.

In an analogous manner, isopropyl iodide gives the / l ⁵ -3 ^ -hydroxy-16a-isopropyl-20-keto-pregnen with a melting point of 159 °.

Example 4

Starting from 5 gl ¹⁶ -3a-acetoxy-ll, 20-diketopregnene and using the procedure described in Example 1, 4.6 g of Sa-acetoxy-loa-methyl-lUO-diketo-pregnane, which after crystallization from a Ether-pentane mixture melts at 157 to 158 °; [a] _B = + 118 ° (chloroform).

Using the procedure described in Example 3, starting from 10 g l ^{1 (i} -3 // - acetoxy-20-keto-pregnen, 8.3 g 3 / i-hydroxy-16u-methyl-20-keto-pregnane are obtained from 203 to 205 ° C. Acetylation gives 3 /? - acetoxy-16a-methyl-20-keto-pregnane with a temperature of 139 to 142 °; [a] o = + 39 ° (chloroform).

In an analogous manner, starting from Ι ⁵ · ^1ΰ -3ρ ', 21-diacetoxy-20-keto-pregnadiene, the l ³ -3, f, 21 -dihydroxy-16a-methyl-20-keto-pregnen, which is obtained in acetylation gives the J ^s -3 / J, 21-diacetoxy-16a-methyl-20-keto-pregnen from 160 to 170 ° (from hexane).

Example 5

30 cm ³ each of dry, peroxide-free tetrahydrofuran and dry toluene are mixed with 10 cm ^{3 of} a 2.14 molar methyl magnesium iodide solution (prepared with a large excess of magnesium from 4 g of magnesium shavings. 3.2 cm ^{3 of} methyl iodide and 53 cm ^{3 of} ether and distilling off the greater part of the ether) ' combined in a nitrogen atmosphere and heated until the temperature in the mixture is 78 °, with 17 cm ^{3 of} solvent distilling off. After cooling to 25 ^{° C.} , 100 mg of dry copper (1) chloride are added and the mixture is stirred with the Grignard mixture for 5 minutes. By distilling off the solvent and by taking three samples of the reaction mixture of 4 cm ³ each, its volume is reduced to 41 cm ³ . The sample taken at the end of the pretreatment develops 20.7 cm ^{3 of} methane with 25% ammonium chloride solution, which corresponds to a Grignard complex content of 9.47 mmol in the reaction mixture. A solution of 1.6 g of 16-dehydro-progesterone in 30 cm ^{3 of} toluene is now allowed to flow in all at once at -10 to 0 "and, after the external cooling has been removed, for 30 minutes

10 to - 12 respond. The work-up takes place by mixing with excess ammonium chloride solution with the addition of a little sodium thiosulfate. Taking up in benzene, drying and distilling off the solvents in vacuo. At the Mixing the crude product with a little ether becomes 1.2 g of crystalline 16u-methyl-progesterone obtain. The chromatographic purification of the mother liquor yields a further 0.25 g. The one from n-hexane recrystallized product melts at 137-138. . · - ,,,, 14 400. IR spectrum: 5.87 μ (20-ketone)

and 5.98 6.17 ·>. (H-3 ketone).

Isopropyl magnesium iodide is used instead of methyl magnesium iodide. that's how you get it 16i! -Isopropyl-progesterone from a temperature of 108 to 109 °.

Example 6

To a Grignard solution. produced from 0.4 g of magnesium and 1.1 cm ^{3 of} methyl iodide in 25 cm ^{3 of} ether, ν earth 50 cm ^{3 of} tetrahydrofuran while watching. The greater part of the Grignard compound is thereby precipitated as a colorless powder. By heating with stirring, 35 cm ^{3 of} solvent are distilled off, as a result of which the ether is largely removed from the reaction mixture. The suspension, cooled to 20 °, is mixed in a nitrogen atmosphere with vigorous stirring first all at once with 0.1 g of copper (l) chloride and immediately thereafter at the same temperature within 3 minutes with a solution of 3.58 g ίο J ¹⁶ - 3 /? - Acetoxy-20-keto-allopregnen added in 20 cm ^{3 of} tetrahydrofuran. The yellow-colored reaction mixture is stirred ^{for a further 1} 1/2 hour at room temperature and then treated dropwise with a solution of 1.1 cm ^{3 of} acetyl chloride in 10 cm ^{3 of} tetrahydrofuran. The reaction mixture, which has become colorless again, is stirred after half an hour of stirring at room temperature with 50 cm ^{3 of} ether and 30 cm ^{3 of} aqueous, saturated ammonium chloride solution. The aqueous layer is separated off in a separating funnel. The tetrahydrofuran-ether solution is washed with 10% sodium thiosulfate solution and again with ammonium chloride solution, dried with magnesium sulfate, evaporated and freed from the solvent as completely as possible by heating to 80 ° for 2 hours in a high vacuum.

The glassy amorphous residue weighs 4.17 g. The IR spectrum of this product and the enol titration with bromine shows that 90 to 95% of theory consists of a mixture of the isomeric J ^{17 (20)} -3 / ?, 20-diacetoxy-16a-methyl-allopregnenes in the 20 position . The two isomeric enol acetates can be largely separated by crystallization from pentane. If the 4.17 g of amorphous substance is dissolved in 7 cm ^{3 of} warm pentane and left to stand in the refrigerator for a few hours, a fraction which melts at 102 ° first crystallizes. Another fraction which melts at 140 ° can be obtained from the concentrated mother liquor.

According to analysis, these two fractions have the same gross formula C26H40O4 and are 100% pure enol acetates after titration with bromine. At the mixed melting point they show a depression of around 20 ^c . In the IR spectrum, the isomer melting at 140 ° has an intense, broad band in the 5.75; j. region, a less intense inflection at 5.87 μ and a band at 8.45 μ of medium intensity. The IR spectrum of the isomer melting at 102 ° shows a split double band in the 5.75 ^ region, also an inflection at 5.87 μ and a relatively weak band at 8.45 μ.

Example 7

If, as described in Example 6, a Grignard solution of 0.4 g of magnesium and 1.1 cm ^{3 of} methyl iodide is added, after 0.1 g of copper chloride has been added, a solution of 3.56 g of ^{I 5} - ^le -3 / ^ - acetoxy -20-keto-pregnadiene in 20 cm ^{3 of} tetrahydrofuran is added and then acetylated with 1.1 cm ^{3 of} acetyl chloride, which is obtained after work-up as described in Example 6. 4.2 g of amorphous crude product. This is dissolved in 8 cm ^{3 of} pentane. The solution is left to ^{stand for hours at -3:} and then 3.82 g of crystals (79% of theory) which melt at 95 to 98 ° are obtained. Based on the analysis and the IR spectrum, they consist of a mixture of the two isomeric J ⁵ - "(20) -3 / i, 20-diacetoxy-16" -methyl-pregnadienes in the 20-position. The IR spectrum

this mixture shows, among other things, broad, intense bands at 5.75 and 8.1 μ, which correspond to the acetate groups can be assigned, and further characteristic bands at 5.93, 8.37 and 8.46 μ of medium intensity. Based on the IR spectrum, the mother liquor roughly consists of the above crystals 70 to 80% from the same enol acetate so that the overall yield is about 95%.

In an analogous manner, 2.95 g of a crude product are obtained from 2.70 g of J ^{5 '16} -3jS-acetoxy-ll, 20-diketo-pregnadiene, which contains about 93% of the two isomers / l ⁵ - ¹⁷ ( ²⁰ ) - Contains 3 _/ S, 20-diacetoxy-l-l-keto-16a-methyl-pregnadiene. For identification purposes, alkaline hydrolysis can be used to obtain the ⁵ -3 /? - hydroxy-11, 20-diketo-16a-methyl-pregnene with a melting point of 198 ° to 199 ° (from acetone-hexane).

Example 8

If 3.1 g of 16-dehydroprogesterone, dissolved in 20 cm ^{3 of} tetrahydrofuran, are reacted with the Grignard compound of 0.267 g of magnesium and 0.72 cm ^{3 of} methyl iodide in accordance with the procedure described in Example 6 and worked up accordingly, this gives a product is obtained in about 90% yield which, according to the IR spectrum, consists mainly of the mixture of the two isomers in the 20-position _z j4, i7 (20) .3.Keto-16a-methyl-20-acetoxy-pregnadienes. For identification, a sample of this is converted into the 16a-methyl-progesterone described in Example 5 by hydrolysis for 1 hour with methanolic hydrochloric acid (10 ml of methanol + 0.5 ml of concentrated hydrochloric acid) at room temperature.

Example 9

190 cm ^{3 of} absolute tetrahydrofuran are added to a solution of methyl magnesium iodide in 80 cm ^{3 of ether prepared from 1 g of magnesium, and 150 cm 3 of} solvent are then distilled off within half an hour. The cooled to 20 ° residual solution is first treated with 250 mg cuprous chloride and then at a bath temperature of 20 ° within 1 Ii ¹ minutes with a solution of 6.75 g ¹⁶ J -3ß, lla-diacetoxy-20-keto-50 in allopregnen cm ^{3 of} absolute tetrahydrofuran were added while rinsing with 10 cm ^{3 of} tetrahydrofuran. The temperature rises to 29 ° and the reaction mixture turns yellow. ^{After stirring for 30 minutes, a mixture of 3 cm 3 of} acetyl chloride and 25 cm ^{3 of} tetrahydrofuran is added dropwise again with cooling with a bath at 20 ° over the course of 1% minutes, the temperature rising to 28 ° and the color changing from yellow to gray. The mixture is then stirred for 40 minutes at room temperature, cooled to 5 ° and 30 cm ^{3 of} saturated ammonium chloride solution, 50 cm ^{3 of} ether and 30 cm ^{3 of} water are allowed to flow in one after the other. The contents of the flask, which consists of two clear layers, are ^{rinsed with 100 cm 3 of} ether into a separating funnel, whereupon they are shaken well, the aqueous phase is separated off and this is ^{extracted again with 75 cm 3 of} ether. The organic phases are extracted one after the other twice with 50 cm ³ molar sodium thiosulfate solution, a mixture of 50 cm ³ saturated sodium chloride solution and 15 cm ³ saturated sodium hydrogen carbonate solution and twice with 50 cm ³ saturated sodium chloride solution, dried with magnesium sulfate and evaporated first at normal pressure and then under a water jet vacuum. The residue is dissolved in xylene, evaporated in vacuo and this operation is repeated again. The solution of the oil thus obtained in 50 cm ^{3 of} hexane is filtered through 8 g of aluminum oxide (activity III). It is rewashed with 250 cm ^{3 of} hexane, the eluate is evaporated in a water-jet vacuum and the residue is dried in a rotary evaporator for IV2 hours at 80 ° and 0.05 mm pressure. Considerable amounts of a fragrant oil are distilled off. The remaining, practically colorless varnish, the weight of which is 8.6 g, is dissolved in 10 cm ^{3 of} pentane and left to stand for several days at -15 °. Then the precipitated crystals are filtered off, washed with cold pentane and dried at 80 ° and 0.05 mm pressure for 4 hours. 4.7 gzl of ¹⁷ ( ²⁰ ) -3ftlla, 20-triacetoxy-16a-methyl-allopregnene are obtained as a stereoisomeric mixture with a melting point of 123.5 ° to 129 °. As a result of its easy solubility, there are still considerable amounts of the enol acetate mentioned in the mother liquor. The IR spectrum of the crystallized enol acetate recorded in methylene chloride shows, among other things, the following characteristic bands: at 5.78 μ with inflection at 5.73 μ and weak shoulder at 5.86 μ (acetates and enol double bond); 8.11 µ (acetates).

If 6.70 g of A ^{5 '16} -3ß, 11 a-diacetoxy-20-keto-pregnadiene are reacted in a completely analogous manner with methylmagnesium iodide and then with acetyl chloride, a crude product that is difficult to crystallize is obtained, which is about 80% from the two isomeric zl ^{5 '17} ( ²⁰ ' -3 ^, l la ^ O-triacetoxy-loa-methylpregnadienes; in the IR spectrum it shows the expected bands, which are hardly distinguishable from those of the above allopregnene compound.

Example 10

190 cm ^{3 of} absolute tetrahydrofuran are added to a solution of methyl magnesium iodide in 80 cm ^{3 of ether prepared from 1 g of magnesium, and 150 cm 3 of} solvent are then distilled off within half an hour. The remaining solution, cooled to 10 °, is first rinsed with 250 mg of cuprous chloride and then at a bath temperature of 20 ° within 45 seconds with a solution of 7 g of ¹⁶ -3 S-acetoxy-ll, 20-diketo-allopregnation in 50 cm ^{3 10 cm 3 of} tetrahydrofuran were added to absolute tetrahydrofuran while rinsing. The temperature rises to 31 ° and the reaction mixture turns yellow. ^{After stirring for 30 minutes, a mixture of 3 cm 3 of} acetyl chloride and 25 cm ^{3 of} tetrahydrofuran is added dropwise again with cooling with a bath at 20 ° over the course of 1% minutes, the temperature rising to 28 ° and the color changing from yellow to gray. The mixture is then stirred for 40 minutes at room temperature, cooled to 10 ° and 30 cm ^{3 of} saturated ammonium chloride solution, 50 cm ^{3 of} ether and 30 cm ^{3 of} water are allowed to flow in one after the other. The flask content, which consists of two clear layers, is rinsed ^{into a separating funnel with 100 cm 3 of} ether, whereupon maji is shaken well, the aqueous phase is separated off and this is ^{extracted again with 75 cm 3 of} ether. The organic phases are successively ^{washed twice with 50 cm 3 of} 1 molar sodium thiosulfate solution, a mixture of 50 cm ^{3 of} saturated sodium chloride solution and 15 cm ^{3 of} saturated sodium hydrogen carbonate solution and twice with 50 cm ^{3 of} saturated sodium chloride solution

409 709341

shaken out, dried with magnesium sulfate and evaporated first at normal pressure and then under a water jet vacuum. The residue is dissolved in xylene, evaporated in vacuo and this operation is repeated again. The solution of the oil thus obtained in 50 cm ^{3 of} hexane is filtered through 8 g of aluminum oxide (activity III). It is rewashed with 250 cm ^{3 of} hexane, the eluate is evaporated in a water-jet vacuum and the residue is dried in a rotary evaporator for IV2 hours at 80 ° and 0.05 mm pressure. Considerable amounts of a fragrant oil are distilled off. The remaining, practically colorless varnish is dissolved in 14 cm ^{3 of} pentane, left to stand for 20 hours at 0 °, whereupon the precipitated crystals are filtered off and washed with cold pentane. 6.2 g / l ¹⁷ < ²⁰ '-3 ^, 20-diacetoxy-II-keto-16a-methyl-allopregnene are obtained as a stereoisomeric mixture with a melting point of 154 to 163 °. Renewed redissolving from 34 cm ^{3 of} methanol increases the melting point to 164 to 165.5 °. The IR spectrum of the crystallized enol acetate recorded in methylene chloride shows bands at 5.73 + 5.77 μ (acetates); 5.85 µ (11-ketone) and 8.13 + 8.24 µ (acetates).

In a completely analogous manner, ^{the crystallized mixture of the two isomers in the 20 position is obtained from the zl 16} -3a-acetoxy-ll, 20-diketo-pregnen / I ^{17 '20)} -3a, 20-diacetoxy-l l-keto- loa-methyl-pregnene in about 90% yield. For identification, a sample of this is converted into the 3a-acetoxy-16a-methyl-11,20-diketo-pregnane described in Example 4 by hydrolysis for 1 hour with methanolic hydrochloric acid (10 ml methanol + 0.5 ml concentrated hydrochloric acid) at room temperature.

Example 11

12.75 g of 16-dehydro-progesterone are dissolved in 200 cm ^{3 of} absolute toluene under nitrogen and cooled to 10 °. ^{In the course of 50 minutes, 265 cm 3 of} a 0.39 molar suspension of methylmagnesium iodide complex in tetrahydrofuran, which contains 500 mg of copper (l) chloride, are added at 9 ° to 11 ° with stirring. The content of the Grignard complex is determined as described for the production of 16a-methyl-progesterone. After a further 5 minutes of reaction time, a sample of the reaction mixture taken after decomposition (with ammonium chloride solution with the addition of a little sodium thiosulfate, taking up in benzene, drying and evaporation of the solvents in vacuo) provides an infrared spectrum which shows the disappearance of the 6.33 ^ band of the / J ¹⁶ shows -20-ketone, while the 6,18 ^ band of J ⁴ -3-ketone is still preserved.

The reaction mixture is now, 10 to 20 minutes after the addition of the Grignard suspension is complete, in the course of a minute, at 10 to 15 ° with a solution ^: 6 cm ^{3 of} acetyl chloride in 50 cm ^{3 of} tetrahydrofuran are added again after a further 20 minutes of reaction time cooled to 10 ° and separated by adding a mixture, precooled to 5 °, of 80 cm ^{3 of} 25% strength ammonium chloride solution and 25 cm ^{3 of} 25% strength sodium thiosulphate solution. After a few minutes of stirring, the aqueous layer is separated off and shaken out once with benzene, which is also used to extract further aqueous washing solutions. The organic layer is washed again with ammonium chloride-sodium thiosulphate solution (same amount as above) and then with 100 cm ^{3 of} ammonium chloride solution. The slightly cloudy, combined organic solutions can be clarified and dried by stirring twice with anhydrous sodium sulfate. The crude product remaining after filtration and evaporation in vacuo, which consists of about 80% of the mixture of the isomeric 1 oa-methyl-progesterone-20-enol acetates, provides 2.6 g of crystals of one isomer, which, from ether, on addition of ether redissolved, melt at 178 to 180 °. P239 ^ c = 15 500. IR spectrum: 5.72 and 8.21 µ (acetate), 5.98 µ (3-ketone and enol) and 6.17 µ (. ^ - double bond).

By chromatography on magnesium silicate, known under the trade name Florisil, and Eluting with a hexane-acetone (95: 5) mixture, 7.2 g of the after the IR spectrum of pure enol acetate mixture obtained, which, however, only slowly and partially crystallized. A very small amount of unreacted 16-dehydro-progesterone can be obtained from the later fractions to be isolated.

Example 12

^{600 cm 3 of} tetrahydrofuran are added to a Grignard solution prepared from 4 g of magnesium and 15 cm ^{3 of} methyl iodide in 300 cm ^{3 of} absolute ether, and the ether and excess methyl iodide are then completely distilled off. 800 mg of cuprous chloride are then added to the suspension, which has cooled to 20 °, while stirring in a stream of nitrogen, and then, within 20 minutes, a solution of 10 g of ^{I 5-1 (i} -3 _{l of} d-hydroxy-21-acetoxy-pregnadien-20-one in 100 cm ^{3 of} absolute tetrahydrofuran are added.After 30 minutes of stirring, the mixture is cooled to 0 °, 200 cm ^{3 of} an aqueous ammonium chloride solution and then ether are carefully added to the residue (12.8 g) of the organic solution washed with water, dried and evaporated It is acetylated for 20 hours with a mixture of 15 cm ^{3 of} pyridine and 30 cm ^{3 of} acetic anhydride. After adding water, it is evaporated in vacuo and taken up in ether. The ethereal solution is washed successively with dilute hydrochloric acid, water, dilute sodium carbonate solution and water, and then dried By redissolving the residue from methanol, 6.75 g of des / l ⁵ -3jS, 21-diacetoxy-16a-methylpregnen-20-one with a melting point of 155 ° to 170 ° are obtained. Recrystallized from acetone-hexane rt, the compound melts at 158 to 170 °. [«]? = + 1.4 ± 2 ³ (c = 0.738 in chloroform). IR spectrum: 5.71 µ (21-acetate), 5.78 µ (strong, 20-ketone + 3-acetate) and 8.15 µ (acetate).

Claims (6)

Patent claims: 1. A process for the preparation of 16a-alkyl steroids of the Pregnan series by treating / J ¹⁶ -20-keto-pregnenverbindungen with alkylmagnesium halides in the presence of copper (l) halides, characterized in that the reaction with the alkylnagnesium halide and the copper (l ) halide in the presence of tetrahydrofuran and in the absence of alkyl halide, the 20-metal formed 180 Enolate decomposed with hydrolyzing or acylating agents and optionally in the so 3- or 3- and 21-position hydroxyl groups in known compounds obtained Esterified way. 2. The method according to claim 1, characterized in that the obtained 20-metal enolate decomposed with a dilute acid or ammonium chloride. 3. The method according to claim 1, characterized ge ίο indicates that the 20-metal enolate obtained with an acylating agent, in particular a carboxylic acid halide, decomposed. 4. The method according to claim 3, characterized in that the obtained 20-metal enolate decomposed with a lower fatty acid halide, especially with acetyl chloride. 5. The method according to claim 1, characterized in that one / l ^IÖ -3 / i-hydroxy-l 1,20-diketo-allopregnen, A ^ie -3ßJ la-dihydroxy-20-ketoallopregnen, / J ¹⁶ -3a-hydroxy -l 1,20-diketo-pregnen, / I ¹⁶ - 3ß - hydroxy - 20 - keto - allopregnen, J ^{5 '16} -3 /? - hydroxy-20-keto-pregnadiene, 1 ⁵ · ^1Η -3 / ;, 21-dihydroxy-20-keto-pregnadiene, l ⁵ - ^1li -3 / ^ - hydroxy-ll, 20-diketo-pregnadiene or l ⁵ - ^Ui -3 / lla-dihydroxy-20-keto-pregnadiene or esters of these Compounds used as starting materials. 6. The method according to claim 1, characterized in that 1 ⁴ - ^I6 -3,20-diketo-pregnadiene is used as the starting material. Legacy Patents Considered:
German patents No. 1,142,362, 1,147,579. When the application was announced, three priority documents were displayed.