DE1211183B - Process for the preparation of 13beta-n-propyl-18-nor-steroids - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

GERMAN

PATENT OFFICE

EDITORIAL

Int. α .:

C 07c

German KL: 12 ο - 25/04

Number:
File number:
Registration date:
Display day:

R32183IVb / 12o
February 27, 1962
24 ·. February 1966

The invention relates to a method of manufacture new 13jß-n-propyl-18-nor-steroids of the general formula

CH ₂ - CH ₃

Process for the production of
13 /? - n-Propyl-18-nor-steroids

where R is oxygen or a free or esterified ¹ S hydroxy group, ie of 3,17-dioxo-10/3-methyl-13/3-n-propyl-Zl ⁴ ' ⁹ ( ¹¹ ) -gonadiene (Ic) and

gonadiene (Ia) and esters of the latter.

These new compounds have particularly inter- esting ^ao pharmacological properties. So has 3-oxo-10 ^ -methyl-13/3-n-propyl-17i3-hydroxy-zl ^4-9 W-gonadien twice as large as the corresponding normal androgen ^ 13-methyl derivative. In addition, they represent precursors of the 13/9-n-propyl-18-nor- ^a 5 derivatives of the androstane, pregnane or spirostane series. They allow easy access to the 18-ethyl homologues of the cortisone steroids.

The process according to the invention, the reaction sequence of which is shown in the scheme, consists in that, in a manner known per se, a 3,5-dioxo-ISβ-n-propyl-IT / S-acyloxy- ^ S-seco-Zl ⁹ ( ¹⁰ > -gonen is selectively ketalized in the 3-position in the presence of an acidic catalyst, the compound obtained reacts with a methyl halide after the action of an alkali metal alcoholate, the keto function in the 3-position of the 10/3-methyl-4,5-seco-J ^{9 obtained} ( ¹¹ '-gonenverbindung by _hydrolysis; acidic, aqueous medium releases the <obtained 5-diketo compound effective by switching cyclized an alkaline agent with simultaneous hydrolysis of the Esterfunktion in position 17 and optionally the formed 3-oxo-10 / - methyl? -13 / 3-n-propyl-17/3-hydroxy-zl ⁴ ' ⁹ ( ¹¹ ) -gonadiene esterified with a functional derivative of a mineral acid or an organic acid or with an acidic oxidizing agent to 3,17-Οϊοχ n-propyl -zl ⁴ > ⁹ ( ^{1: l} > -gonadiene oxidized.

The essential steps of the process according to the invention thus consist in the selective blocking of the 3-keto function of a 3,5-dioxo-13/3-n-propyl-17 /? - acyloxy-4,5-seco-Zl ⁹ ^ °> -gonens - (II) by ketalization,

Applicant:
Roussel-Uclaf, Paris

Representative:

Dr. F. Zumstein,

Dipl.-Chem. Dr. rer. nat. E. Assmann

and Dipl.-Chem. Dr. R. Koenigsberger,

Patent Attorneys, Munich 2, Bräuhausstr. 4th

Named as inventor:

Dr. Gerard Nomine, Noisy-le-Sec, Seine;

Dr. Robert Bucourt,

Clichy-sur-Bois, Seine-et-Oise;

Andre Pierdet, Noisy-le-Sec, Seine (France)

Claimed priority:

France of March 1, 1961 (854 250)

in the introduction of a methyl group in the lOjS position of the 3,5-dioxo-13 ^ -n-propyl-17 ^ -acyloxy-4,5-seco-Zl ⁹ < ¹⁰ ) -gonen-3-ketal (III), with simultaneous shifting of the double bond to position 9 (11),

in the release of the keto function in the 3-position by hydrolysis,

in the cyclization by Crotonosieren of 3,5-dioxo-10j5-methyl-13 ^ -n-propyl-17 _j i3-acyloxy-4,5-seco ^ l ^{9 <u>} -gonens (V) in an alkaline medium with simultaneous saponification of the ester function in the 17-position and optionally
in the oxidation of the alcohol group in position 17 to the ketone.

The starting compound is advantageously the • 3,5-Dioxp-17 ^ -benzoyloxy-13 / Sn-propyl-4,5-seco- ^ l ⁹ ( ¹⁰ ) gonen, which is obtained by the process described in Belgian patent 599,342 can be.

According to a preferred embodiment of the process according to the invention, the formation is effected of the 3-ethylene valley with. a solution of methylethyldioxolane in benzene by heating to refluxing. The ketalization is caused by the Presence of a small amount of a strong acid, such as para-toluenesulfonic acid, catalyzes and

609 509/406

1 211

3 4

appears almost exclusively on the one of interest. The TR spectrum (carbon disulfide) is confirmed

Keto function in 3-position. 100% conjugated ketone.

The enolization of the keto function in the 5-position Arrive, * · r w η - dfia ^ o

after blocking the 3-keto function, _Ώ ', f JL,, - "", ττο _ΟΛΟ /

of an alkali metal tert-amylate. like potassium-tert- s »' ^Be 5 ^ec ^ ^net ''" «Χ * οα # sofa,

amylate, carried out under reflux in toluene. ' β ^ ^{α & η} _: \ ^{c / 4} > ⁸ / o »** ^b ' ² / *

The subsequent Methyh'erung is used in the The connection was in the literature so far

Licher temperature by means of methyl iodide in an inert not described.
Solvent, especially toluene, carried out.

One works preferably at 20 ^° C. Io level B: S-ethylenedioxy-S-oxo-lOß-methyl-

Then the hydrolysis of 13 / ^ n-propyl-17 / ^ benzoyloxy-4,5-seco-Zl ⁹ ( ^u > -gonen (IV)

3-Äthylenketal by heating in dilute aqueous. _TT " _T,, . , ".

Acetic acid, especially in 75% acetic acid. ^a ) Production of potassium tert-amylate

The cyclization by crotonizing is brought into a previously dried multi-necked flask

Heat to refluxing boiling in an over 15 one in succession 40 ecm over sodium dried

schüssigen methanolic solution of KOH through toluene, 5 ecm redistilled tert-amyl alcohol and

guided. then about 2 g of freshly cut potassium. You cook

The oxidation of the released alcohol function in ^{1 1} J ₂ hours under reflux in a nitrogen atmosphere

17-position is made at room temperature by means of chromium and then allowed to come to room temperature. Of the

acid anhydride, preferably in acetic acid, through-ao titer of this potassium alcoholate solution is about normal.

The following example explains the process of ^b ) preparation of the alkali compound
Invention. According to the method, instead of the in a carefully dried multi-necked flask with 17-benzoate, other 17-esters, for example a stirrer and nitrogen inlet tube, can be brought in with the acetate, naphthoate, terephthalate, the hexa-25 200 mg of S-ethylenedioxy-S-oxo-IS / Sn-propyl-H / J-benhydrobenzoate, halobenzoates, nitrobenzoates or zoyloxy-4,5-seco-, d ⁹ ( ¹⁰ > -gonen (III), which use pivalates in 2 ecm of toluene. Also can be dissolved as enolization Then all at once under nitrogen, alkali metal alcoholates other than the potassium substance atmosphere 0.5 ecm of the tert-amylate prepared as above are used, for example aiko-potassium tert-amylate solution or cesiums. 30 flasks in an oil bath of 140 ⁰ C. The solution becomes

The specified temperatures are quickly brought to refluxing boil in degrees Celsius and

expressed. The melting points are left at this for 15 minutes. It appears a minor one

Maquenne block determined. . Precipitate that forms on cooling to room temperature reinforced.

Example 1 35. _c ) alkylation

{sion of the Kahumdenvat within 5 minutes

Stage A: S-ethylenedioxy-S-oxo-O ^ -n-propyl- _{480 mg} methyl iodide in 1 ecm toluene add. It results

17 /? - benzoyloxy-4,5-seco-Zl ⁹ ( ¹⁰ ) -gonen (Iir) ₄₀ first a complete solution of the mixture,

Bringing a mixture of 1 g of 3,5-dioxo and after 5 minutes a precipitate occurs which 13 / - n-propyl-17 |? S-benzoyloxy-4,5-seco-PLN ^{9 (10>} - Gonen amplified. Stir the reaction mixture 17 stun 10 cc of benzene, 10ccmMethyläthyldioxolanund20mg the at 2O ⁰ C in a nitrogen atmosphere. After this para-toluenesulfonic quickly rückfiießenden time adds water and extracted twice with boiling. After 10 minutes refluxing boiling cools 45 70 ecm of ether. The ethereal solution is also quickly decanted and poured into 20 ecm of a gene, combined and washed three times with 40 ecm of 5% aqueous sodium bicarbonate solution. After water. The dried ethereal phase is used for extraction, washing and drying of the organic Brought dry.

The solution is distilled to dryness and 1.1 g is obtained. 212 mg of crude S-ethylenedioxy-S-oxo of an oil, the S-ethylenedioxy-S-oxo-IS / Sn-propyl-50 10/3-methyl-17 / S-benzoyloxy-13 ^ -n-propyl-4,4-seco-17/9-benzoyloxy-4,5-seco-J represents ⁹ < ¹⁰ > -gonen. By J ⁹ < ^{1: 1} > -gonen, thus a quantitative yield.
Chromatography and subsequent crystallization. The compound has so far been used in the literature

sizing from isopropyl ether and methanol is not described,
an analysis product that ^{melts at 113.5 0} C and in UV spectrum (ethanol):
colorless prisms crystallized in benzene and 55 _{3 00Q u} · ₀ , _n -m »_ _Οδ ο.
Alcohol soluble in isopropyl ether and methanol little ^Ama * ~~ ^{bls ZiO m} '£ ί "~ * 4th

are soluble and insoluble in water. om ™ SiS ¹ Z iA '

It has the following physical constants: ' ^ZVLm V-> ni. _m - 4.0.0.

The spectrum shows the absence of the conjugate

UV spectrum (ethanol);

250 ηιμ (shoulder), E ₁ ¹ *, = 386;

280 ηιμ (shoulder), E ₁ ¹ L = 22. ⁶ 5

The absorption at 237 ηιμ corresponds to 99% conjugate. The connection is sufficiently pure for the constricted Ketone. application in the further course of the proceedings.

5 6

Stage C: S ^ Dioxo-10 ^ -methyl - ^ - n-propyl- One adds 0.78 ecm of one to the solution thus obtained

17 /? - benzoyloxy-4,5-seco - ^ <"> - gonen (V) oxidation mixture of

212 mg of the compound obtained in stage B, c) 0.61 g of chromic anhydride,

are dissolved in 15 ecm of 75% acetic acid. The 5 0.48 ecm of water and

homogeneous solution is under nitrogen for 1 hour to 4> ⁸ ecm acetic acid

60 ⁰ C brought. It is then cooled to 20 ^° C., neutral to.

Sized with a solution of sodium bicarbonate and the reaction is allowed to 80 minutes at about 20 ° C

extracted with ether. The combined essentials go on with stirring. The mixture remains

Phases turn brown with water until they are neutral. At the end of the reaction, 3.2 ecm are added

wash, dried over anhydrous sodium sulfate, methanol to destroy the excess reaction

and evaporated to dryness after filtration. tion agent and allowed to stir for 15 minutes

193 mg of 3,5-dioxo-10) 3-methyl-13 ^ - are obtained in this way. The greenish solution is through

n-propyl-17/3-benzoyloxy-4,5-seco-J ⁹ < ^{1: 1} ) -gonen, which neutralizes a sodium bicarbonate solution and then

corresponds to a quantitative yield. 15 extracted exhaustively with twice 100 ecm of ether.

The product is used for no further purification. The unified ethereal solutions are made with

the following process stage is used. Water until the washing water is neutral

In the literature, the compound has hitherto been washed, dried, filtered and finally under vacuum

not described. brought to dryness.

ao This gives 104 mg of a yellow resin, what

Stage D: S-Oxo-10 / S-methyl-1Sß-n-propyl- corresponds to a yield of 80%. The product will

17j5-hydroxy-Zl ⁴ < ⁹ ( ¹¹ ) -gonadiene (Ia) purified by pasting with isopropyl ether and thoroughly

Recrystallized from ethyl acetate by heating and cooling.

193 mg of the prepared according to step C are dissolved. A first yield of 22 mg is obtained in this way

Compound in 19.3 ecm of a 0.5 normal methanol 35 165 ⁰ C melts. One brings the mother liquors to

see potassium hydroxide. It is brought under nitrogen dryness for 1 hour and 77 mg of a resin is obtained which is attached

atmosphere for refluxing boiling. The Siücagel solution is chromatographed. After eluting with Me-

shows an orange color. It is brought under vacuum to the ethylene chloride, which contains 1% acetone, is obtained

Dry and then absorb in 40 ecm of water. The 47 mg of the purified product after evaporation,

occurring precipitate is obtained twice with 70 ecm 30.

Ethyl ether extracted. The essential phases are corn 18.5 mg pure 3.17Οί10 ^% 1133

^{'9 (11)} -gonadien with water until neutrality of the washing waters overall pyl- / d. ⁴

wash, dry, filtered and vacuum to give the total yield of the pure product

Evaporated to dryness. therefore 30%.

This gives 130 mg of a brittle yellow 35 The 3,17-Dioxo-10iS-methyl-13 _J 8-n-propyl-Zl ¹ ' ⁹ ( ¹¹ ) -

Resin. The yield is 96.5%. gonadia has not yet been mentioned in the literature

This resin is chromatographed on magnesium letters. It results in the form of a colorless,

silicate. After eluting with methylene chloride, the 0.5% crystalline solid, which is soluble in chloroform, in

Contains acetone, a colored ethyl acetate is obtained after evaporation which is sparingly soluble and insoluble in water.

loose resin, which is obtained from isopropyl ether and then from 40 F. = 165.5 ⁰ C, [α] ?? = +173 ± 2 ° (c - 0.5%, Me-

Recrystallized ethyl acetate. The pure ethanol is obtained.

jS-n-propyl - ^ - hydroxy-zH ⁹ ^) - i _R _s _pe ktrum:

^ in the form of colorless Prta «, which in ^ p

Acetone, benzene and chloroform very soluble, m Aiko- 45,

hol and ether are soluble and insoluble in water. ^aer

F. = 135.5 ° C, [α] ο "= + 82 ± 1 ° (c = 0.5%, Me- The spectrum is different from that of the

ethanol). 13 /? - methyl steroids; the curve of the circular dichroic

_v mus can practically be superimposed on those who

uv-bpeKtrum. 50 one starting from the 3,17-dioxo-zl ⁴ ' ⁹ ( ¹¹ ) -androstadien

Shows the presence of the grouping 3-Oxo- A *. receives

The IR spectrum confirms the proposed. The UV spectrum shows the presence of a

Structure. conjugated ketone 3-Oxo-Zl ⁴ ( ^B >.

Analysis: C ₂₁ H ₃₀ O ₂ = 314.45. Analysis: C ₈₁ H ₂₈ O ₂ = 312.43.
Calculated ... C 80.20%, H 9.61%, ⁵⁵ Calculated ... C 80.72%, H 9.03%;

found ... C 80.3%, H 9.5%. found ... C 80.7%, H 9.0%.

The connection was still in the literature so far

not described. Example 3

Esterification of S-Oxo-10 / S-methyl-IS / S-n-propyl-

Example 2 17 _J S-hydroxy-Zl ⁴ ' ⁹ ( ¹¹ ) -gonadiene

Production of S ^ -Dioxo-lO / J-methyl-lS / in-propyl-, ^ ^an * ° ^St ° '? ⁵ ? F J ^eS λ ^ ΨίΚ

^S i ^4. «(") - gonadiene (Ic) 3-oxo-10 _i S-methyl-13 _; Sn-propyl-17 _j S-hydroxy-z

65 gonadiene (Ia) in 2 ecm benzene and 0.5 ecm pyridine.

130 mg of the 3-oxo prepared according to Example 1 are then added dropwise with stirring 0.2 ecm

10 ^ -methyl-13 _j Sn-propyl-17 | 3-hydroxy- / d ⁴ ' ⁹ < ^{1: l} ) -gona- freshly distilled benzoyl chloride to. One maintains

diens (Ia) are dissolved in 16.2 ecm of pure acetic acid. Stir for 2 hours at room temperature. After this

Time is mixed with 2 ecm of ice-cold water and stirs vigorously for 1 hour. The aqueous phase is decanted and the benzene phase is washed three times with ice-cold Water.

The benzene phase is dried over sodium sulfate, filtered and then an equal volume of petroleum ether is added. Place on an ice bath overnight. The benzoate of S-oxo-lOß-methyl-lSjö-n-propyl-17/5-hydroxy-J ^{4> 8} ( ^{i: l} > -gonadiene crystallizes, and it is separated off by filtration, washed in several portions with 1 ecm petroleum ether and dried, giving 0.190 g of S-oxo-lOß-methyMSiS-n-propyl-l? ^ hydroxy-Zl ⁴ ' ⁹ ( ^{: ll} ) -gonadiene benzoate with a melting point of 195 ° C.

Another recrystallization from a mixture of benzene and petroleum ether does not change the melting point.

Pharmacological test report on the physiological testing of 3-Ketq-17jff-hydroxy-13 / fai-pro ■. pyl-18-nor-J ⁴ ' ⁹ ( ¹¹ ) -androstadien

The androgenic and anabolic effects of the procedure available substance was by subcutaneous application for 10 days after the Test by H e rs h b e r g e r (cf. Proc. Soc. Exp. Biol. Med., 83 [1953], p. 175), with the iü The values given in the following table resulted in:

Total dose V · body weight g
before! "afterwards _;

Seminal vesicles

mg

levator ani, If

Comparison group

^ ("^ Testosterone _j

13 (Sn-Propyl-10/3-methylgonadien-17β-ol-3-qn
testosterone

// means the ratio between the weight of the fresh levator ani and the body weight, related to 100 g body weight of the animal.

The table shows that 13/3-n-propyl · · /J4.e(ii)-gonadien-17j8-ol-3-on has an androgenic effect, which is increased by increasing the weight of the seminal vesicles to about Shows double compared to the use of zl ⁹ ( ¹¹ ) -Dehydrotestosterone. Further, the compound shows a more superior than a third anabolic effect against ^ 9 (ii) _ie _S t _osteron _ The process product is also active, which was also used for comparative purposes at comparable doses when testosterone.

Claims (2)

Claims: ' 1. Process for the production of 13 /? - n-Propyl-18-nor-steroids the general formula ■ CH ₂ -'CH ₃ 45 496
544
500 46
45
46 87
88
89
79 5.1
56,
119
113 0.16
0.36
0.48
0.45 where R is oxygen or a free or esterified hydroxyl group, characterized in that a 3,5-dioxo-13 /? - n-propyl-17/3-acyloxy-4,5-seco-Zl- ⁹ ( ¹⁰ > -gönen is selectively ketalized in the 3-position in the presence of an acidic catalyst, the compound obtained reacts with a methyl halide after the action of an alkali metal · ·. Alcoholate ^ the keto function in the 3-position of the 10 / J-methyl ^ S-seco -J ^ "i-gonenverbindungen released by hydrolysis in an acidic, aqueous medium, the resulting <5-diketo compound by the action of an alkaline agent with simultaneous saponification of the ester function in the 17-position cyclic and optionally the formed 3-Οχό-10 | S- methyl-13 ^ -n-propyl-17 ^ -hydroxy-ZI ⁴ ' ⁹ ( ^u > gonadiene esterified with * a functional derivative of a mineral acid or an organic acid or with an acidic oxidizing agent to 3,17-dioxo-10 | 3-methyl-13/3-n-propyl-J * - ⁹ ( ⁿ ) -gonadiene is oxidized. 2. The method according to claim 1, characterized in that the ketalization is carried out in the 3-position using methylethyldioxolane. ■ ... Publications under consideration:
Angewandte Chemie, Vol. 72 (1960), p. 729;
^; Comptes xendus; Vol. 250: 1293/1294 (1960). 1 sheet of drawings 609 509/406 2.66 ® Bundesdruckerei Berlin