DE1246725B - Process for the preparation of 2-alkyl-1, 11alpha-oxido-3-keto-delta 1,4, -androstadie - Google Patents

Description

UNI> ESRE1 ^ BL1K GERMANY

GERMAN

PATENT OFFICE

EDITORIAL

Int. CL:

C07C

07 J 1föv _u

German class: 12 ο -25/04

Number: 1 246 725

File number: L 489511V b / 12 ο

Filing date: October 5, 1964

Display day: 1.0. August 1967

, fr

The invention relates to a process for the preparation of new 2-alkyl-l, ll * -oxido-3-keto-J ^{l> 4} -androstadienes of the general formula (I), in which R is a lower alkyl group with 1 to 4 carbon atoms, R "is hydrogen or a lower alkyl group with 1 to 4 carbon atoms and R 'is a free or esterified hydroxyl group or together with R" is a keto group. If R 'represents an esterified hydroxyl group, the acyl radical is that of an aliphatic, cycloaliphatic or araliphatic carboxylic acid with 1 to 12 carbon atoms, ζ. B. acetic acid, propionic acid, trimethyl acetic acid, heptanoic acid, cyclopentyl propionic acid, phenylacetic acid, succinic acid or hexahydrobenzoic acid.

The process according to the invention consists in that, according to the reaction ^{scheme, a 2-alkyl-II «-hydroxy- / I 1> 4} -3-ketosteroid of the general formula (III) in which R, R 'and R" are the above Have meaning, with chlorine or bromine, expediently with exclusion of light, halogenated ao and the resulting 2-halo-2-alkyl-1A, ll "-oxidoil ⁴ -3-ketosteroid of the general formula (IT), in which R, R 'and R "have the abovementioned meaning and Hal means chlorine or bromine, treated with a hydrogen halide-releasing agent in a manner known per se.

In the starting compound of the general formula (III), when R 'is a free hydroxyl group and R "is hydrogen, the oxidation of the hydroxy group also take place during the halogenation, and there are then compounds of the formula (II) and then obtained the formula (1) in which R 'and R "together represent a keto group.

The compounds of the general formulas (II) and (I) have interesting biological activity. Compounds of both structures have good anabolic properties compared to the parent compounds Retained activity, but have lost androgenic activity to a very noticeable extent. The ratio of their anabolic activity (measured by the well-known muscle levator ani test) to the androgenic activity (measured by the behavior of the prostate and seminal vesicles) is very high. Compounds of structure (I) have an even more favorable ratio of anabolic to other activity as compounds of structure (II).

In addition, the connections between the two structures have an established anti-inflammatory effect Activity (determined by the granuloma test) which is very similar to that of hydrocortisone.

The starting compounds of the general for-process for production

of 2-alkyl-l, ll "-oxido-3-keto- Λ V-androstadien" - · -—

Applicant:

Laboratorio Farmaceuticp Lofarma S. a. S., Milan (Italy)

Representative:

Dr.-Ing. A. van der Werth and Dr. F. Lederer, Patent Attorneys, Munich 8, Lucüe-Grahn-Str. 22nd

Named as inventor:

Pietro Blasina,

Carlo Scolastico, Milan (Italy)

Claimed priority:

Italy of October 5, 1963 (39 738)

mel (IH) is obtained from the corresponding 2 <% - Alkyllla-hydroxy-3-keto-steroidal zl ^ by dehydrogenation with selenium dioxide or selenious acid in a suitable solvent such as t-butanol or amyl alcohol, at room temperature to 15O ⁰ C, preferably at the boiling point of the solvent. The dehydration can also take place microbiologically under the action of microorganisms of the type of Corynebacterium simplex, Bacillus sphaericus or Didymella lycopersici under aerobic conditions.

The halogenation of the Ausgaugsverbindungen the general formula (III) is carried out at temperatures not above 40 ⁰ C, preferably in the range of from -35 to +5 ⁰ C, airi best in the presence of an organic solvent. Examples of solvents that can be used are ethers such as diethyl ether and dioxane, halogenated hydrocarbons such as carbon tetrachloride, tertiary amides such as dimethylformamide, tertiary organic bases such as pyridine, collidine or lutidine, lower aliphatic acids such as formic acid, acetic acid, Propionic acid or butyric acid. The solution of the steroid (III) is treated with the halogen, which is preferably also dissolved in a solvent, such as one of the above-mentioned ethers, halogenated hydrocarbons or aliphatic

709 620/574

3 4

Acids. The molar ratio of halogen to steroid and shows [<x] g, = -31 "CHCl ₃ , y £ S ° ^M - 250 πΐμ

can vary between 1: 1 and 2: 1, but should (ε = 15 100) and IR bands at 3400,1661,1618 and

Do not exceed 1.1: 1 if there is a free secondary 1605Cm ^-1 .

Hydroxy group present on carbon atom 17 1 g of the starting compound 2.17 * -Di-

is, if not the simultaneous oxidation of the hydroxy-5 methyl-11 ", 17 /? -dih.ydroxy- <d ^li4 -androstadien-3-ons

group itself is striven for to a keto group, in carbon tetrachloride — pyridine (4: 1)

The halogenation is suitably resolved in the absence. 1.1 molar equivalents of chlorine gas are then in

of light to perform. the reaction ^{vessel at -10 0} C in the dark

The inventive method can lead with one. The mixture is left in the dark,

whole series of 2-alkyl-II <x-hydroxy-3-keto-io until the chlorine absorption is complete, and then becomes

J ^l - * - androstadienes are carried out. It includes poured into water, filtered off and the precipitate

thus also the halogenation of 2-Αϋψ1-11 «, 17β-αί- dried. After crystallization from methylene chloride

hydroxy-3-keto-J ^{1> 4} -androstadienes and the ent- hexane becomes 2 ", 17at-diniethyl-2 /? - chloro-17/3-hydroxy-

speaking 17-ester of the general formula (III). l 'llcx-oxido / 1 ⁴ -androsten-3-one was obtained (Formula IV).

In particular, the process of the invention can »5 melting point 222 to 224 ° C; [«]!? = -60 ° (c = 1 ° / ₀ ,

be carried out with 17-acyloxy derivatives of chloroform); UV: y _maz = 246 mμ (e = 9900); IR-

Carboxylic acids with up to 12 carbon atoms such as bands at 3400, 1692 and 1647 cm " ¹ ,

those already in connection with the general a """."" m ~ <- <υ n nt.

t ^ ι / t \ ij / analyze iur ν ^ αιΉαον / βν ^ ΐ

Formula (I) were mentioned. '· Z Λ _Λ , τ, -, _oe ™

On the other hand, when compounds of the general ₂ o are found ... C 69.26, H 7.85, Cl 13.35, O 9.74%;

Formula (III) in which R 'calculates a free hydroxy group ... C 69.12, H 8.01, Cl 13.16, O 9.72 · / ,.

and R "is hydrogen, used as starting materials 250 mg lithium chloride become 500 mg 2«, 17a-di-

and at least 2 molar equivalents of halogen methyI-2) S-chloro-17 /? - hydroxy-l «, ll <% - oxido- / l ⁴ -andro-

are used, halogenated ester-3-one can also be added to 15 ml of dimethylformamide. the

bonds (II), in which the substituents R 'and 35 mixture will stand for 45 minutes to settle

R "together represent ketone oxygen, preserved, then poured into water and filtered. The

so isolated precipitate becomes on aluminum oxide

Finally, the inventive method relates to chromatographed, where 2.17 <x-dimethyl

also the halogenation of 2,17 "-dialkyl-II", 17 (8-di-17j5-hydroxy-la, ll ".oxido-J ^ -androstadien-S-one

hydroxy-3-keto-zJ ¹ ^ -androstadienes and the ent- 30 receives. Melting point 226 to 23O ⁰ C; [«] ²⁰ ° = + 14.9 °;

Speaking 17-ester of the general formula (III), UV: γ _ηαχ = 243 ηιμ (ε = 13,500) and 292 πιμ

in which R and R "lower alkyl groups with 1 to (« = 6500); TR band at 3400, 1680, 1639 and

4 carbon atoms mean. 1905 cm ' ¹ .

According to the invention, the halo-

generated derivatives (II) by treatment with a 35 B is ρ ie 1 Il
Reagent which split off hydrogen halide

can be converted into the corresponding 2-alkyl-l, ll <x-oxido lg 2-ethyl-ll ", 170-dihydroxy- <d ¹ ' ⁴ -androstadien-J ^x ' ⁴ -3-keto steroids (I). A tertiary 3-one is dissolved in acetic acid. 1 molar equivalent of chlorine organic base, e.g. As collidine, lutidine or pyridine i _n carbon tetrachloride is added dropwise at one or lithium chloride in dimethylformamide, can be used for 40 temperature of -30 ⁰ C for 5 hours trains · this purpose may be used. The halogen water .-- give. The mixture is carried out in the dark at -3O ⁰ C. Substance cleavage is preferably carried out at temperatures above room temperature for a total of 10 hours, generally left. When the product is obtained, as described in the example at the boiling point of the game I used, 2% - ethyl-2 /? - chlorine-la, ll "-oxy solvent. The reaction can be obtained on all halo 45 do -17 / 9-hydroxy-zJ ^ -androsten-3-one (forged compounds of the general V defined above). Melting point 184 to 187 ° C; IR band can be applied to my formula (II). 3450, 1660 and 1647 cm- ¹ ; UV: Xm _0x -246 νημ

The following examples explain the invention (e = 9500).

proper procedures. 250 mg of lithium chloride become a solution of

Example! ⁵ ° ^ ^{0 mg} 2 "-Ethyl-2 / I-chloro-1", llix-oxido-17 ^ -hydroxy-

zJ ⁴ -androsten-3-one in 15 ml of dimethylformamide ge

To prepare the starting compound are given. 2-ethyl-17 /? - hydroxy-1 «, lla-oxido-J ¹ ' ⁴ -andro-

4.8 g of 2 ", 17a-dimethyl-lluc, 17 / J-dihydroxy-J ⁴ -andro- stadien-3-one is, as described in Example I, iso-

sten-3-one, dissolved in a mixture of 190 ml. Melting point 165 to 170 ° C; UV: λ «« * = 242ηιμ

tert-butanol and 4.8 ml of glacial acetic acid, with 4.8 g of SeO ₂ and 55 (e = 12,900) and 290 ηιμ (ε = 6200).
4.8 g Hg added. The reaction mixture is boiled

24 hours at reflux with stirring under N, Example Hl
then a further 4.8 g of SeO _{2 are} added; after further

The mixture is cooled for 24 hours, anddiluted with ethyl acetate a) lg2,17 «-dimethyl-lla, 17 / S-dihydroxy- ^ ^l ' ⁴ -andro-diluted and filtered. The solution is 60 stadien-3-one to dryness, dissolved in acetic acid, is evaporated with 1.1 moles. The residue is Essigester Open equivalent bromine in acetic acid (lm) solution in taken, and the obtained solution is treated in succession -1O ⁰ C. The mixture is _s solution, and 5% to stand at -10 ⁰ C with other NaI solution, Na ₂ 0 S _a strength in the dark for 8 hours, then washed NaHCOa solution. After evaporation of the poured into water, the precipitate is filtered off and solvent, the residue is _{dried on Al 2} O ₃ chromium-65. After chromatography, the product is matographed. The obtained, crystallized from ethyl acetate from chloroform-hexane and 2 / 5,17a-dicrystallized 2,17 «- dimethyl - ΙΙα, Π /? - dihydroxymethyl-2 "-bromo-17/3-hydroxy-1, ll" -oxido-J * -andro-J ^ -androstadienO-one melts at 223 to 225 ° C sten-3-one obtained (formula VI ). Melting point 157

up to 160 ° C (decomposition); [ac] o = -112 ° (c = 0.8% in CHCl ₃ ); UV: λ, _ηαχ at 250 ΐημ, ε = 7500.

Analysis for C ₂₁ H ₂₉ O ₃ Br:

Found ... C 61.8, H 7.30%;
calculated ... C 61.61, H 7.14%.

b) A solution of 290 mg of the obtained 2j5,17a-dimethyl ^ '- bromo-17jS-hydroxy-l "ll" -oxido-J ⁴ -androsten-3-one, dissolved in 4 ml of collidine is, for 45 minutes refluxed.

The mixture is then cooled, poured into water and extracted with methylene chloride. Of the The extract is then washed with dilute hydrochloric acid and with water, dried over sodium sulfate and concentrated to dryness.

The residue is dissolved in benzene-chloroform (5: 5) and chromatographed with Al ₈ O ₈ . By eluting with benzene-chloroform (3: 7), after crystallization from acetone-hexane, 190 mg of 2,17 * -dimethyl-17 /? - hydroxy-l, ll <% - oxido- / ¹ '* -androstadiene-3 -on obtained (Formula IX). Melting point 226 to 230 ⁰ C; [x] _D = + 14.9 ° (c = 1% in CHCl ₃ ); UV: X _max = 243 τημ, «= 13,500 and = 292 τημ, ε = 6500.

»5 is washed with water and concentrated to dryness in vacuo. After chromatography of the residue over aluminum oxide, 2-methyll.llÄ-oxido-Λ ¹ ' ⁴ -androstadiene-3,17-dione is obtained (formula X). Melting point 255 to 60 ° C; [λ] λ = + 107 ° (0.8% in CHCl ₃ ); UV: X _max = 243 ηΐμ, ε = 11,300 and X _max = 292 πψ, ε = 4800; IR (Nujol): bands at 1733, 1678, 1637 and 1613 er- ¹ .

Claims (6)

Patent claims: 1. Process for the preparation of 2-alkyl, II "-oxido-3-keto-J ^li4 -androstadienes of the general formula (I) R ' Analysis for C ₂₁ H ₂₈ O ₃ : Found ... C 76.61, H 8.48%;
calculated ... C 76.79, H 8.59%. B e i s ρ i e1 IV 190 mg ^ lTiX-dimethyl-lla-hydroxy-n / S-acetoxy- / l ^l - ⁴ -androstadien-3-one are dissolved in pyridine-propionic acid. 1.1 mol of chlorine in propionic acid are added, and the mixture is allowed to stand at -10 ⁰ C in the dark for 8 hours. Proceed as described in the previous examples and obtain 2 (%, 17 <x -dimethyl-2j3-chloro-17 /? - acetoxyl ", ll <x-oxido-J ⁴ -androsten-3-one (formula VI). Melting point: 220 to 4 ° C; [<x] d = -302 ° (c = 0.27% in CHCl ₃ ). No <r hydroxy group bands in the IR spectrum. 250 mg of lithium chloride are added to a solution of 500 mg of 2 ", 17-dimethyl -2β- chloro-17 /? -Acetoxyl", 11 <x-oxido- <d ⁴ -androsten-3-one in 15 ml of dimethylformamide. 2,17 "-Dimethyl-17/9-acetoxyl <x, II" -oxido-J ^{I> 4} -androstadien-3-one is isolated as described in Example 1. Melting point 190 to 194 ° C; UV: X _max = 243 ηιμ («= 13100) and 291 τημ (e = 6200). Example V a) 2-Methyl-Ig * ll, 17-dihydroxy-£ J ^{1 't} -androstadien-3-one, dissolved in dimethylformamide is treated with 2.2 molar equivalents of chlorine in acetic acid at -1O ⁰ C. The solution is kept in the dark at -10 ° C. for 7 hours, then poured into water, the precipitate is filtered off and dried and crystallized from acetone-hexane, with 2 /? - chloro-2 "-methyl-1", llix-oxido -zl ⁴ -androstene-3,17-dione is obtained (formula VIII). Melting point 224 to 6 ° C; UV: _{λ max} = 244 ΐημ, ε = 10 400; [*] /> = + 24.2 ° (c = 0.99% in dioxane). b) 250 mg LiCl are added to 500 mg of the 2 "- methyl - 2ß - chloro - Ιλ, ΙΙλ - oxido - Δ ⁴ - androstea-3,17-dione obtained, which are dissolved in 15 ml of dimethylformamide. The mixture is refluxed for 45 minutes, then poured into water and extracted with methylene chloride. The extract R - ^ in which R is a lower alkyl group with 1 to 4 carbon atoms, R "is hydrogen or a lower alkyl group with 1 to 4 carbon atoms and R 'is a free or esterified with an aliphatic, cycloaliphatic or araliphatic carboxylic acid with 1 to 12 carbon atoms or together with R" denote a keto group, characterized in that a 2-alkyl-II <x-hydroxy-.d ¹ ' ⁴ -3-ketosteroid of the general formula (III) R ' HO R " R.
OK in which R, R 'and R "have the aforementioned meaning, halogenated with chlorine or bromine, expediently with exclusion of light, and the 2-halo-2-alkyl-l«, ll (X-oxido- / I ⁴ -3- ketosteroid of the general formula (II) O - in which R, R 'and R "have the aforementioned meaning, with a hydrogen halide Means, especially with a tertiary organic base or with lithium chloride in Dimethylformamide, treated in a manner known per se. 2. The method according to claim 1, characterized in that there is the halogenation in one organic solvent, especially in an ether, a chlorinated hydrocarbon, a Nitrogen-containing heterocyclic base or a lower aliphatic carboxylic acid. 3. The method according to claim 1 or 2, characterized in that the molar ratio of Axisgangssteroid to halogen in the halogenation is about 1: 1 to 1: 2. 4. The method according to any one of the preceding claims, characterized in that the Halogenation if the molar ratio of halogen to starting steroid is no higher than 1.1: 1 R 'in the starting compound represents a free secondary hydroxyl group. 15th 5. The method according to any one of claims 1 to 3, characterized in that the halogenation the molar ratio of halogen to parent steroid is equal to or greater than 2: 1 when R 'in of the starting compound represents a free secondary hydroxyl group and if simultaneously with the halogenation in 2-control leads to an oxidation of the hydroxyl group on carbon atom 17 a keto group is sought. 6. The method according to any one of the preceding claims, characterized in that the Elimination of hydrogen halide at a temperature which is higher than room temperature, preferably at the boiling point of the hydrogen halide splitting agent used. 1 sheet of drawings 709 $ 20/574 7.67 Θ Bundesdruckerei Berlin