DE1593349B - Process for the preparation of Des-A-5-oxo-9, l 1-gonadienes - Google Patents

Description

The invention relates to a process for the preparation of cyclopentanopolyhydro-naphthalene derivatives which for the sake of simplicity, referred to in the manner of the nomenclature commonly used in steroid chemistry be, d. i.e., their names are derived from the corresponding tetracyclic compounds, where the prefix "Des-A" is put in front.

The "Des-A" steroid derivatives obtainable according to the invention are represented by the general formula I:

R OX

being the corresponding 10-hydroxymethylenenone of the general formula III

HO - H, C

in which R and X, as also in the following, have the meanings given above, in a manner known per se Formylated according to Vilsmeyer - Haack,

20th

wherein R is an alkyl radical having 1 to 6 carbon atoms and X is hydrogen, a saturated or unsaturated alkyl radical with 1 to 5 carbon atoms containing one oxygen atom between 2 carbon atoms or an acyl radical of an organic carboxylic acid having 1 to 18 carbon atoms mean.

In the general formula I, the alkyl radical R advantageously denotes methyl, ethyl, propyl, isopropyl, Butyl or isobutyl. ,

The new compounds of general formula I are used as intermediates in the production of 2-oxa steroids of the general formula

30th

(III)

obtained, this by reaction with a substituted p-quinone to formyldienone of the general Formula IV

(IV)

35

40

45

used, wherein R and X have the meaning given above, and in particular a significant one have anabolic effect and an androgenic effect.

The inventive method for preparing the compounds of general formula I is thereby characterized in that a 5-oxo-des-A-9-gonen of the general formula II

(Π)

dehydrated in a manner known per se, the aldehyde group of which is removed with the aid of an alkali metal borohydride or of lithium aluminum tri-t-butoxyhydride in a manner known per se selectively for the hydroxymethyldienone sought of formula I reduced.

The formylation is carried out according to the method of Vilsmeyer-Haack (Ber. 6OB [1927], p. 119) accomplished. One uses, for example, the dimethylformamide-phosphorus oxychloride complex, however it is clear that other complexes of other substituted formamides, such as from N-methyl-N-phenylformamide or N-piperidino-N-methylformamide, with other chlorinating agents, such as phosgene, sulfuryl chloride or phosphorus pentachloride, can be applied in the same way.

The reaction is carried out in an organic solvent, for example methylene chloride, working at or near ambient temperature.

The dehydrogenation of 10-hydroxymethylenenone of the general formula III is carried out with the aid of a substituted p-quinone. examples are

2,3-dichloro-5,6-dicyano-p-benzoquinone,
2,3-dibromo-5,6-dicyano-p-benzoquinone,
2,3,5,6-tetrachloro-p-benzoquinone,
2,3-dicyano-5-chloro-p-benzoquinone and
2,3-dicyano-p-benzoquinone.

It is advantageous to work in dioxane.

This reaction will generally take place at or near ambient temperature carried out under an atmosphere of an inert gas such as nitrogen.

That in the selective reduction of the aldehyde function of the diene compound of the general formula The alkali metal borohydride used in IV is preferably sodium or potassium borohydride. One works in a solvent such as aqueous dioxane with slight cooling and uses the theoretical Amount of borohydride.

A variant of the process according to the invention is characterized in that an enamine is used general formula V

(V)

R, -N

wherein R and X have the meaning given above, R _{2 is} an alkyl radical with 1 to 8 carbon atoms, R _{3 is} an alkyl radical with 1 to 8 carbon atoms or R ₂ and R ₃ together are an alkylene chain with 4 to 5 carbon atoms or an alkyleneoxyalkylene chain with 4 carbon atoms , condensed as a starting product in a manner known per se with formic acid-acetic acid mixed anhydride, the resulting iminium compound of the general formula VI

R OX

(VI)

35

subjected to acid hydrolysis in a manner known per se, the corresponding 10-hydroxymethylenenone of the general formula III

45

(IH)

is obtained and then proceeds according to the manner specified in claim 1 further.

The acyl radicals of the organic carboxylic acids are derived from saturated or unsaturated aliphatic acids or cycloaliphatic carboxylic acids or of aromatic or heterocyclic carboxylic acids, of Cyclopentyl, cyclohexyl or phenylacetic acid or propionic acid, of phenoxyalkanoic acids, of furan-2-carboxylic acids, 5-t-butylfuran-2-carboxylic acid or ^ -ketocarboxylic acids.

The starting products of the process according to the invention can for example according to the in the French patent 1 234 734. the Belgian U.S. Patent 599,342 and U.S. Patent 3,168,530.

example 1

Production of the 5-oxo-10-hydroxymethyl

13 / S-methyl-17 / S-benzoyloxy-des-A-9,11-gonadiens

(or the S-oxo-10-hydroxymethyl-n / S-benzoyloxy-

des-A-9,11-estradiene)

Level a

5-Oxo-l O-hydroxy methylene-13 / S-methyl-

17 /? - benzoyloxy-des-A-9 (ll) -gonen (or 5-oxo-

10-hydroxymethylene-17/3-benzoyIoxy-

des-A-9 (ll) -östren)

In 6.2 cm ^{3 of} anhydrous dimethylformamide are added dropwise with stirring at ambient temperature 15 cm ^{3 of} anhydrous phosphorus oxychloride, and the solution is left to stand for 2 hours.

On the other hand, 3 g of 5-oxo-13 /> - methyl-17ß-benzoyloxy-des-A-9-gonen (described in French patent specification 1,234,734) are ^{suspended in 3 cm 3 of} methylene chloride.

While the temperature of the suspension is kept at 16 ^° C., 6 cm ^{3 of} the dimethylformamide-phosphorus oxychloride complex prepared above are introduced with rapid stirring, without ^{exceeding 20 °} C., and the mixture is stirred for 10 minutes.

The reaction mixture is then poured into ice water, stirred for a few minutes, extracted with benzene and then with ether, and the extracts are washed with water. It is decanted, then 2 cm ^{3 of} formic acid are added, and the mixture is stirred ^{under a nitrogen atmosphere for about 1 1/2 hours.} The solution obtained is washed with an aqueous tartaric acid solution, then with water, 5% aqueous potassium carbonate and then again with water.

The expected product is then obtained by washing with a 0.28N aqueous ice-cold potassium hydroxide solution isolated. After acidifying the potassium salt with sulfuric acid to a pH of 3 to 4, Extraction with ether, drying and evaporation of the solvent gives a residue which crystallized by adding ethanol.

After recrystallization in isopropanol with 10% water is pure 5-oxo-lO-hydroxymethylene-13 /? - methyl-17 /? - benzoyloxy-des-A-9 (ll) -gonen, melting at 129-130 ^0th C isolated in 34% yield.

The product is insoluble in water, dilute aqueous acids, in cold and alcohols Isopropyl ether sparingly soluble and in dilute aqueous alkalis, alcohols in the warm, ether, Chloroform, methylene chloride, toluene and ethyl acetate are soluble. It gives with iron (III) chloride an intense blue reaction.

Analysis: C ₂₂ H ₂₄ O ₄ (352.41).

Calculated ... C 74.97, H 6.86, 0.18.16%;
found .... C 75.0, H 7.0, O 18.1%.

The connection has not yet been described in the literature.

Level B.

5- Oxo-10-formyl-13 ^ -methyl-17 /? - benzoyloxydes-A-9,11-gonadiene

At ambient temperature, 10.6 g of 5-oxo-10-hydroxymethylene-13 / S-methyl-17/3-benzoyloxydes-A-9 (II) -gonen are dissolved in 106 cm ^{3 of} anhydrous dioxane

dissolved, it is cooled slightly, then 7.15 g of 2,3-dichloro-5,6-dicyano-p-benzoquinone are in the course of a few minutes is added and the reaction mixture is stirred under a nitrogen atmosphere for 1 hour.

It is filtered, the insoluble part is washed with methylene chloride, the hydrate is in Poured water and extracted with ether.

The extracts are successively with a saturated aqueous sodium bicarbonate solution, one Washed 1 N sodium hydroxide solution, water and salt water.

It is dried and distilled in vacuo. The residue crystallizes on trituration with ether.

It is filtered off with suction, and 4.14 g of 5-oxo-O-formyl-13 / J-methyl-17 /? - benzoyloxy-des-A-9, l 1-gonadiene, ie 39%, are obtained, which after recrystallization Ethanol has a melting point = 137 to 138 ^° C .; [a] _D = -62.3 ° (c = 0.94%, chloroform).

IR spectrum (chloroform):

CHO at 1690 cm " ¹ and CH at 2750 cm" ¹
C = O at 1665 cm- '
C = O at 1593 cm- 'and 1543 cm "'
Benzoate at 1715 cm " ¹ and 1279 cm"'

UV spectrum:

1. Dioxane

/. "," At 230 ηΐμ, * ■ = 19,000
and 303 to 304 πΐμ, »■■ = 21,000

2. Ethanol and 1/10 sodium hydroxide solution
;., "" At 231 ηΐμ, «■ · = 21 000
and 259 Γημ, <■■ = 14,000

and 333 πΐμ, e = 7 900

Analysis: C ₂₂ H ₂₂ O ₄ (350.40).

Calculated ... C 75.40, H 6.33%;
found .... C 75.7, H 6.5%.

The product is sparingly soluble in alcohol and ether and soluble in chloroform.

The connection is not described in the literature.

after recrystallization in ethyl acetate is added to the ether, 2.6 g of 5-oxo-10-hydroxymethyl-13/3-methyl-17 /? - benzoyloxy-des-A-9, l 1-gonadiene in a yield of 56% with a m.p. = 134 to 135 ⁰ C; [a] ₀ = -69.2 ° (c = 0.9%, chloroform).

The product is insoluble in water, sparingly soluble in ether and soluble in alcohol and chloroform.

IR spectrum (chloroform):

C = O and C = C at 1645 cm " ¹ and 1605Cm ^-1 OH associated between 3560 and 3400 cm" ¹

UV spectrum in ethanol:

/ ,,, "230 ΐημ,, = 15 050

?. _max 285 πΐμ, F = 25 500

Analysis: C ₂₂ H ₂₄ O ₄ (352.41).

Calculated ... C 74.97, H 6.86%;
found C 74.8, H 6.8%.

Level C

5-Oxo-l O-hydroxy methyl-13 / J-methy 1-

17 / J-benzoyloxy-des-A-9, ll-gonadiene (or 5-oxo-

1 O-hydroxy methyl-17 /? - benzoy loxy-

des-A-9,11-estradien)

4.63 g of 5-oxo-10-formyl-13/5-methyl-17 /? - benzoyloxy-des-A-9,11 -gonadic-i in a mixture of 46 cm ^{3 of} anhydrous dioxane and 4, 6 cm ^{3 of} water are dissolved, it is cooled to about 5 ° C., and 0.141 g of sodium borohydride are slowly added with stirring under a nitrogen atmosphere.

The mixture is stirred for a further 1/2 hour, then the reaction mixture is poured into water and mixed with Extracted methylene chloride. The extracts are washed with water and then with salt water, dried and distilled to dryness in vacuo.

The residue is dissolved in the minimum amount of benzene-ethyl acetate mixture (2/3) and chromatographed with the same solvent mixture on silica gel.

A crystallized product is obtained which The compound is not described in the literature.

^D B eis ρ ie 1 2

Preparation of 5-oxo-10-hydroxymethylene-13 / i-methyl-17 / f-benzoyloxy-des-A-9 (II) -gonen

(or des 5-oxo-10-hydroxymethylene-17 / i-benzoyloxy-des-A-9 (l l) -estrene) from the

Enamine of S-Oxo-B / i-methyl-n / J-benzoyloxydes-A-9-gonen

1 g of S-pyrrolidyl-B / J-methyl-n / J-benzoyloxy-des-A-5 (10), 9 (l l) -gonadiene, described in French Patent 1,271,997, in 5 cm ^{3 of} anhydrous dioxane, the solution is cooled to a temperature of 10 ⁰ C, then dropwise 0.37 cm ³ of triethylamine and 0.9 cm ³ formic acetic mixed anhydride added (JA.CS, 61, 3355 [1939]).

The reaction mixture is stirred in a nitrogen atmosphere V for ₂ hours at about 10 ^° C., then 2 cm ^{3 of} water are added, and the stirring is continued for a total of 2 hours. Then it is poured into water, extracted with ether, the extracts are washed with ether, an aqueous saturated sodium bicarbonate solution and an ice-cold 1/10 sodium hydroxide solution.

It is acidified with hydrochloric acid, extracted with ether and the extracts are washed as described above and finally with water.
It is dried, filtered, evaporated to dryness, and the residue is crystallized from ethanol, yielding 0.17 g of 5-oxo-10-hydroxymethylene-13 / S-methyl-17/9-benzoyloxy-des-A-9 (II ) -gonen with a melting point = 129 to 130 ⁰ C, which is identical to the compound obtained in stage A of Example 1.

The hydroxymethyldienones corresponding to the general formula I are in the same way obtained when starting from 5-oxo-des-A-9-gonenes of the general formula II or their enamines, which, however, has a different alkyl group in the 13-position carry as the methyl group, for example an ethyl, propyl, isopropyl, butyl or isobutyl group.

Claims (5)

Patent claims: 1. Process for the preparation of des-A-steroid derivatives of the general formula I. HOH ₇ C (I) «ο wherein R is an alkyl radical having 1 to 6 carbon atoms and X is hydrogen, a saturated or unsaturated alkyl radical with 1 to 5 carbon atoms containing one oxygen atom between 2 carbon atoms may include, or denotes an acyl radical of an organic carboxylic acid having 1 to 18 carbon atoms, characterized in that that one has a 5-oxo-des-A-9-gonen of the general formula II 25 R OX (H) in which R and X, as also in the following, have the meanings given above, in a manner known per se Formylated according to Vilsmeyer - Haack, whereby the corresponding 10-hydroxymethylenenone of the general formula III 35 40 (III) 45 obtained, this by reaction with a substituted p-quinone to formyldienone of the general Formula IV 55 (IV) dehydrated in a manner known per se, the aldehyde group of which is removed with the aid of an alkali metal borohydride or of lithium-aluminum tri- 65 t-butoxyhydride, in a manner known per se, selective to the sought-after hydroxymethyldienone of the formula I reduced. 2. The method according to claim 1, characterized in that the formylation by action of the phosphorus oxychloride-dimethylformamide complex is carried out. 3. The method according to claim 1, characterized in that the substituted p-quinone 2,3-dichloro - 5,6 - dicyano - ρ - benzoquinone, 2,3 - dibromo-5,6 - dicyano - ρ - benzoquinone, 2,3,5,6 - tetrachlorop - benzoquinone, 2,3 - dicyano - 5 - chloro - ρ - benzoquinone or 2,3-dicyano-p-benzoquinone. 4. The method according to claim 1, characterized in that the alkali metal borohydride is sodium borohydride or potassium borohydride. 5. Modification of the method according to claim 1, characterized in that one is an enamine of the general formula V R OX (V) wherein R and X have the meaning given above, R ₂ * an alkyl radical with 1 to 8 carbon atoms, R ₃ an alkyl radical with 1 to 8 carbon atoms or R ₂ and R ₃ together an alkylene chain with 4 to 5 carbon atoms or an alkyleneoxyalkylene chain with 4 carbon atoms mean, condensed as the starting product in a manner known per se with formic acid-acetic acid mixed anhydride, the resulting iminium compound of the general formula VI (VI) HOHC subjected to acid hydrolysis in a manner known per se, the corresponding 10-hydroxymethylenenone of the general formula III (HI) is obtained and then proceeds according to the manner specified in claim 1 further. 109 546/458