DE1801389B2 - PROCESS FOR THE MANUFACTURING OF 17 ALPHA-ACYLOXY-20-KETO-STEROIDS - Google Patents

Description

The present invention relates to a new process for the preparation of 17a-acyloxy-20-keto steroids of the pregnan and 19-nor-pregnan series, characterized in that a 20-acyloxy-17a, 20-oxidosteroid of the pregnan or 19-norpregnan series in the presence of an organic sulfonic acid or perchloric acid with the anhydride of an aliphatic one or converting aromatic carboxylic acid.

The steroid residue of the as used according to the invention Starting product can - apart from additional oxido or cyclopropane rings - the Steroid compounds contain common substituents. Examples include free, esterified or etherified Hydroxyl groups, e.g. B. in the 3-, 11-, 16- and / or 21-position, free or functionally modified keto groups, z. B. in the 3- and / or 6-position, preferably lower alkyl groups, e.g. B. in 1-, 7-, 16- and / or 18-position, halogen atoms, e.g. B. in 2-, 4-, 6-, 7-, 9-, 16 and / or 21 position. In addition, the molecule in rings A, B, C and / or D can be saturated or be unsaturated, e.g. B. in 1-, 3-, 4-, 5 (6) -, 5 (10) -, 6-, 9 (11) - and / or 14 (15) position. One if necessary Any 5 hydrogen atom present can have a 5a or 5 / S configuration.

In principle, all aliphatic and aromatic substances are used to carry out the process according to the invention Carboxylic acid anhydrides are suitable, and their selection is essentially determined by what is ultimately desired 17 ester residue in the process product.

The reaction at room temperature or at an elevated reaction temperature takes place in the presence a solvent, the carboxylic acid anhydride used according to the invention in addition to its function as a reaction partner can also lein solvent at the same time. To implement with a homogeneous In order to be able to carry out the reaction mixture, it will in most cases be expedient to additionally carry this out add a solvent. Suitable solvents are all those which act against the according to the invention the reagents used are inert, e.g. halogenated hydrocarbons are listed here, such as methylene chloride, ethylene chloride, carbon tetrachloride, aromatic hydrocarbons such as benzene, or also carboxylic acids, such as acetic acid. The organic sulfonic acid added to the reaction mixture or perchloric acid serves as a reaction catalyst.

When carrying out the process according to the invention, it must be ensured that the starting product is present free hydroxyl groups are acylated at the same time. Free keto groups in the starting product, ζ. Β.

389

present as a 3-keto-A ⁴ grouping may need to be protected before carrying out the process according to the invention, because these too are attacked under the reaction conditions used with the formation of enol acylates.

In the novel process it is possible, on the 17,20-oxido-20-acyloxy-Gruppi _e tion a 17a-acyloxy while achieving technically usable yields in one reaction step to introduce. The smooth course of the reaction was not to be expected without further ado, since it is known that 3,20-diacetoxy-17a, 20-epoxy-5a-pregnane on the one hand by thermal treatment with isomerization of the 17-position side chain in 3ß, 17-diacetoxy-5o, 17a- pregnan-20-one [Turner et al., J. Am. Chem. Soc. 79 (1957) p. 1108] is converted and on the other hand in the acid hydrolysis with z. B. hydrochloric acid can only be converted into 17a-hydroxy-3 /? - acetoxy-5a-pregnan-20-one [German Auslegeschrift 11 17 119] in poor yield.

The following examples serve to further explain the process according to the invention. Unless the starting materials used in the process are not described above, the 20-acyloxy-17a, 20-oxo grouping given in the starting product is introduced in the usual way from corresponding I7a-deoxy-20-keto steroids, e.g. B. by enolization of the 20-keto group with carboxylic acid anhydride in the presence of an acidic catalyst, such as perchloric acid, and subsequent epoxidation of the 17,20 double bond formed using peracids, such as peracetic acid. If the products of the process are also to contain a 16-position alkyl group, the 16-alkyl group and the 20-acyloxy-! 7a, 20-oxo group are expediently introduced simultaneously. ^{A corresponding A ie} -20-ketosteroid is then used as the starting steroid, which is treated in the usual manner with alkylmagnesium halides in the presence of copper-I-chloride, after which the 16a-alkyl- ^{A17 (} 20'-20 metal enolate obtained) is also used decomposed in the usual way with acylating agents, for example with acyichloride in tetrahydrofuran, and finally the Δ ¹ " ²⁰ " double bond is epoxidized with a peracid.

example 1

To 0.40 g of magnesium shavings in 5 ml of abs. A solution of 1.1 ml of methyl iodide in 20 ml of ether is added dropwise to ether over a period of 2 hours. To completely dissolve, the mixture is stirred for a further 0.5 h. Then 50 ml of tetrahydrofuran are added, 35 ml of ether / tetrahydrofuran mixture are distilled off and, after cooling to 20 ^° C., 0.1 g of copper (I) chloride is added. 3.68 g of 3 /? - acetoxy-5 / M6-pregnen-20-one in 20 ml of tetrahydrofuran are added and the mixture is stirred for a further hour.

The reaction mixture is then mixed with 1.1 ml of acetyl chloride added in 10 ml of tetrahydrofuran, stirred for 1 h at room temperature and then in 700 ml stirred in aqueous ammonium chloride solution. The oily product which separates out is dissolved in methylene chloride added, the organic phase with 10% sodium sulfate solution and twice with water washed, dried with sodium sulfate and concentrated to dryness in vacuo: Yield: 5.2 g of oily 3 / ?, 20-diacetoxy-16a-methyl-5/9-pregn-17 (20) -ene.

This enol acetate is dissolved in 30 ml of carbon tetrachloride, while stirring, with 0.41 g of powdered Sodium acetate and 5.8 ml 40% peracetic acid

18 Ol

sets and stirred for 4 Ii at room temperature. The carbon tetrachloride solution is then washed neutral with 10% sodium thiosulphate solution and water, dried with sodium sulphate after filtration and evaporated to dryness in vacuo: Yield: 4.6 g of oily S / I ^ ODi
thyl-5 / i-pregnan.

The raw / y ^ py
ethyl-5 / i-pregnane is dissolved in 23 ml of methylene chloride and heated under reflux for 4 hours in the presence of 2.75 ml of acetic anhydride and 0.69 g of p-toluenesulfonic acid. After cooling to 20 ° C., 3.22 ml of methanol / water (1: 1) are slowly run in and the mixture is stirred for a further 30 minutes. The methylene chloride solution is then washed neutral with dilute sodium carbonate solution and water, and the organic phase is dried with sodium sulfate and evaporated in vacuo. The crude product is recrystallized from methanol: Yield: 3.05 g of 3 / i, 17a-diacetoxy-16a-methyl-5 / - pregnan-20-one, m.p. 200-202 ⁰ C [u] _D + 19.2 ° (CHCl ₃ ). ao

Example 2

10 g of oily S / ^ O-diacetoxy-na ^ O-epoxy-löa-methyl-5 / i-pregnane are dissolved in 50 ml of methylene chloride, mixed with 15 ml of acetic anhydride and 0.1 ml of 70% as perchloric acid and 2 h stirred at room temperature. The methylene chloride solution is then washed neutral with water, concentrated to dryness and the residue is recrystallized from methanol: Yield: 7.1 g of S / J.na-diacetoxy-loct-methyl-S /? - pregnan-20-one; F. 198-202 ⁰ C [a] _D + 19.4 ° (CHCl _3).

Example 3

If in Example I the 4-hour cooking time is replaced by a dissolving reaction at room temperature 7.5 g of 3 / ?, 17 ″ -diacetoxy-16a-methyl-5/5-pregnan-20-one.

Example 4 ₄ "

10 g of Öüges S / ^ O-diacetoxy-na ^ O-epoxy-loa-methyl-5 / J-pregnane are dissolved in 100 ml of glacial acetic acid while warming, mixed with 12 ml of acetic anhydride and 1.5 g of p-toluenesulfonic acid and 4 h heated to 40 to 42 ° C. Hanach, the reaction mixture is cooled, precipitated in ice water, the resulting precipitate is filtered off with suction and washed neutral. After recrystallization of the crude product is obtained 7.35 g of 3ß, 17a-diacetoxy-16 <z-methyl-5 / i- pregnan - 20-one, mp 197-200 ⁰ C; [a] _D + 18.0 ° (CHCU). 5 "

Example 5

10 g öüges / ypy /
ethyl-5 "-pregnane are stirred in a mixture of 50 ml of methylene chloride, 15 ml of acetic anhydride and 0.1 ml of 70% perchloric acid for 2 hours at room temperature and worked up analogously to Example 2: Yield: 7.4 g of 3 / i, 17a-diacetoxy-16 /} - methyl-5a-pregnan.-20-one, m.p. 161-162 ° C.

60 Example 6

10 g of 3 / ?, 20-diacetoxy-17a, 20-epoxy-5 /? - pregnane are stirred in a mixture of 70 ml of carbon tetrachloride, 15 ml of acetic anhydride and 0.1 ml of 70% perchloric acid for 20 minutes at room temperature. ^{Water is then added to 6} S, the mixture is stirred and the organic phase is washed neutral. After concentration to dryness, it is recrystallized from isopropyl ether: Yield: 7.2 g of 3 / ?, 17a-diacetoxy-5βpregnan-20-one, melting point 175 to 176.5 ° C; [a] _D + 3.0 ° (ethanol).

Example 7

2 g of 3 /? - acetoxy-5 /? - pregnan-20-one are in 17 ml Carbon tetrachloride, 3.4 ml of caproic anhydride and 0.02 ml of 70% perchloric acid for 2 hours at room temperature touched. The mixture is then stirred with water, with sodium bicarbonate solution and water washed and dried with sodium sulfate and filtered.

The S / J-acetoxy ^ O-capronyloxy-S / J-pregn-17 (20) -en containing carbon tetrachloride solution is with 0.22 g powdered sodium acetate and 3.1 ml 40% peracetic acid was added and the mixture was stirred at room temperature for 4 h. After that, the reaction solution washed with sodium sulfite solution and water and concentrated to dryness in vacuo.

The oily 3 ^ -acetoxy-20-capronyloxy-17a, 20-epoxy-5 /? - pregnane obtained in this way is in a mixture of 10 ml of methylene chloride, 3.4 ml of caproic anhydride and 0.02 ml of 70% perchloric acid stirred for 30 min at room temperature. Then the .Methylene chloride solution washed neutral with dilute sodium hydroxide solution and water, dried with sodium sulfate, filtered and concentrated to dryness in vacuo. The crude product is determined by preparative thin layer chromatography Purified (cyclohexane / ethyl acetate 7: 3): Yield: 1.3 g of S / S-acetoxy-ntz-capronyloxy-5 /? - pregnan-20-one as oil;

Found: 73.2% C 9.9% H 16.5% O

calc .: 73.4% C 9.6% H 16.9% O

Example 8

10 g of S / ^ O-diacetoxy-Ha ^ O-epoxy-Sa-pregnane are treated analogously to Example 6 in a mixture of 70 ml of carbon tetrachloride, 15 ml of acetic anhydride and 0.1 ml of 70% perchloric acid: Yield: 7.15 g 3 / ?, 17a-diacetoxy-5a-pregnan-20-one, m.p. 198 to 199 ^C C; [a] _D - 9.3 ° (dioxane).

Example 9

9.0 g 3a, ll /? - diacetoxy-5/9-pregnan-20-one become in 80 ml of carbon tetrachloride with 14 ml of acetic anhydride and 0.1 ml of 70% perchloric acid and 2 h at Room temperature stirred. Thereafter, the reaction solution is made with sodium bicarbonate solution and water washed neutral and dried with sodium sulfate.

After filtration, the enol acetate solution thus obtained becomes with 1 g powdered sodium acetate and 15 ml 40% peracetic acid was added and the mixture was stirred at room temperature for 4 h. Then it is done with sodium sulfite solution and water and the organic phase evaporated to dryness in vacuo.

The remaining oily 3a, 1 l / f, 20-triacetoxy-17a, 20-epoxy-5 /? - pregnane is taken up in 70 ml carbon tetrachloride and treated with 15 ml acetic anhydride and 0.1 ml 70% perchloric acid as in Example 6: Yield: ? 7.1g 3a, l Ι / ί-Πα-triacetoxy-5 / - pregnan-20-one, m.p. 209 to 21O ⁰ C; [α] _υ + 54.3 ° (CHCl ₃ ).

Example 10

9.0 g of 3 / 3.2l-diacetoxy-5a-pregnan-20-one analogously to Example 9 via the enol acetal: into the epoxy

5 ⁶

ι a im ι τ wtnxv of 14 2 g ammonium chloride decomposed in 40 ml water,

convicted. There are 10.2 g of 3 ^, 20,21-Tnacetoxy- ^ , nin licheerilhrt and distilled with steam.

17a, 20-epoxy-5a-pregnane obtained as an oil. The residue is taken up in methylene chloride

10 g of 3 ^ 20,21-triacetoxy-17a, 20 ^ poxy-5a-pr _e gnan L> er kuc _ammonium chloride solution and irit

are in a mixture of 70 ml carbon tetrachloride ^^ "S ^ chen. After filtering over

substance, 15 ml of acetic anhydride and 0.1 ml of JO ^ iger sodium sulfate are concentrated in vacuo

Chloric acid treated analogously to Example 6: Yield ^ water ^ ^^ ^ _{54 g} ^. ^ ₍ , _someren

7.0 g ß / i.na ^ l-Triacetoxy-Sa-pregnan ^ O-one, F. 204 "« ^ jaAcetoxy ^ O-benzoyloxy-lOG-mahyl-S / f-

up to 205.5 ° C. pregn-17- (20) -en.

Example 11 1. 12.9 g of this 20-benzoyloxy compound are added, n

, " _{1 <A} 'ι Mfthvlenchlorid dissolved and at 20 C 8.6 g

tg S-methoxy ^ O-acetoxy-Ha ^ poxy-U-nor 154 ml Me £ ^ j ^ j _{(f 0% ig) eingetra} ,, _{s. Ma} *

1,3,5 (10) -pregnatrien is in a mixture of 7 ml ™: ~ Τ, £ ^ _room temperature and destroys the

Benzene, 1.5 ml acetic anhydride unc10 01 m 70% .gerPer- ^^^^ Jfzueabe of 8 m <20% iger

chloric acid analogous to Example 6: yield. ^^^ "g. _It will be cooled about 75 ml methylene 0.69g ^ M ^ IZ ^^^} ^ "^" SSridÄlfcri the residue to 0 ° C

natrien-20-one, m.p. 193 to 194.5 C; [a] _D + 43.10 "JTJj ₆ precipitated m-chlorobenzoic acid suctioned off.

(CHCl ₃ ). _{D the filtrate} is washed with dilute sodium bicarbonate,

Example 12 sodium bisulfite and saturated saline solution and

, g ^ O-diacetoxy ^ O-epoxy- ^ nor-, 3,5 (.O) - ^ £ EaASί

pregnatrien are in 7 ml / «nuAljAohtagoff ^^^^ dry a. This gives 13.6 g dissolved and treated with 1.5 ml acetic anhydride and 0.01 ml 70 / - enj -m Vaicu ^^ ^ .tenzoyloxy-l ^ O ^ poxy-Joaiger perchloric acid analogously to Example 6. Oily * P " ^J

Loot: 0.7 g 3,17a-Diacetoxy-19-nor-l 3 ^ (10> -preg- ^^^ "iogrohem S / J-Acetoxy-M-benzoylnatrien-20-one, F. 194 to 195 ⁰ C; \ a) _D + 34 ° (CHCI ₃ ) - «5 ^ Losungau. ^ ^^ ^ ^^^ _jn ^ _{m |}

Methylene chloride is mixed with 14.4 g of benzoic anhydride

Example 13 _umJ , ^J _{5 g of} p.Toiuolsulfonsäure added and 4 h under

10 g (20-acetoxy-17a.20 < _! Poxy-4-pregiien-3-ylidene> _{: Röck} f'l _u ß heated. After cooling to 20 ^J Cwer-N-pyrrolidinium perchlorate in a Gem.sch _{30 to slowly} 15 ml of methanol / water (1.1) run voj 85 ml of benzene, 15 ml of acetic anhydride and 0.1 ml _{blank and} subsequently stirred for 30 min. One washes _m, t comparable

70 ° /, perchloric acid for 1 h at room temperature, sodium bicarbonate solution and water overall _thinned r neutral stirred then allowed to long to the reaction mixture _and distilled with water vapor. The residue is sam run 10 ml of methanol, stirred for 30 min after, _{jn Met} hylenchlorid added and again with then treated with 0.2 n aqueous-methanolic sodium hydroxide _{35 ver} dilute sodium bicarbonate solution and VV ater gelaugein slight excess and stirred again about _what chen . The organic phase is filtered over 30 min at room temperature. The solution is then anhydrous sodium sulfate and evaporated in vacuo to neutralized with acetic acid, washed with water and a _Troc KNE. The residue is preparative evaporated the organic phase in vacuo. The 17a-acetoxy-4-pregnene-3,20-dione thus obtained _D ünnschichtchromatographie (Cyclonexan / Attieru 1]) is from _{4O au} f _get running. 3.5 g of 3/1-acetoxy-i / akilliiF 2385 at 240 ° C. are obtained in this way

ren 17aAcetoxypg obtained, _{4 au} f _get

Recrystallized ethyl acetate: mp 238.5 to 240 ° C. benzoyloxy

_D. ·. .. UV: _f22B = 14,050; e _m = 910; ε ₂₈₀ = 720.

Example 14 ^22B

From 1.7 g of magnesium shavings in 160 ml of tetra.

hydrofuran is obtained by introducing methyl bromide 45, Example 13

made a Grignatd solution. 80 ml are distilled. _{If the} 3/3-acetone obtained according to Example 14 is used

Tetrahydrofuran from, cools to 15 ° C and gives 0.28 g of _oxy . ₂ o-benzoyloxy-17,20-epoxy-16o-methyl-5 (9-preg-

Copper-I-chloride too. Immediately afterwards, a _{stam with benzoic anhydride is} left with the equivalents

Solution of 10 g of 3/9-AcCtOXy-S / - 16-pregnene-20-one in _{ten men Ess} i _gs äureanhydrid order, obtained by

70 ml of tetrahydrofuran at 30 ⁰ C and stirring is continued 5 <> _rativer thin layer chromatography 3.4 g of 3 / f,

1 h at 30 ⁰ C after. i _7a. diacetoxy-16a-methyl-5 ^ -pregnan-20-ori and 3.75g

⁰ C then is cooled to O and from 0 to 3λ. _Acetoxy . 17 «-benzoyloxy-16a-methyl-5 / i-pregnan-

5 ⁰ C a solution of 6.8 ml of benzoyl chloride in 40 ml of ^ _0n

Tetrahydrofuran was added dropwise. The mixture is stirred for 1 h at 0 ^° C. ' ₆₉₀

after. The reaction mixture is UV with a solution. F ₂₂₉ = 14.230, ε ₂₇₂ a -, aeo

Claims (1)

Claim: 1801 Process for the preparation of 17a-acyloxy-20-ketosteroids of the pregran and 19-nor-pregnane series, characterized in that manein20-acyloxy-17a, 20-oxidosteroid of the Pregnan or 19-norpregnan series in the presence of an organic sulfonic acid or perchloric acid with the Reacts anhydride of an aliphatic or aromatic carboxylic acid.