DE1212080B - Process for the preparation of 20-tert-amino-20-alkyl steroids and salts thereof - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

GERMAN

PATENT OFFICE

EDITORIAL

Int. α .:

C07c

German class: 12 ο -25/05

Number: 1212 080

File number: R35990IVb / 12o

Filing date: August 27, 1963

Opening day: March 10, 1966

The invention relates to a process for the preparation of new 29-tert-amino-20-alkyl steroids general formula I.

CH ₃

C-N

in the form of the free bases or corresponding salts. In formula I, R and R _{1 are} lower alkyl, aryl or aralkyl radicals, R _{2 is} an alkyl radical having 1 to 4 carbon atoms, X is an oxygen atom or

"OR ₃

R _{3 is} a hydrogen atom or a substituted or unsubstituted lower acyl radical and YH ₂ or

Process for the preparation of 20-tert-amino-20-alkyl steroids and salts thereof

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. Daniel Bertin, Montrouge, Seine;
Dr. Lucien Nedelec, Clichy-sous-Bois,
Seine-et-Oise (France)

Claimed priority:
France of August 27, 1962 (907 856),
of May 3, 1963 (933 624)

where these compounds can either be saturated and then belong to the 5/3 Pregnan series or if X is an oxygen atom, they can contain a double bond in the 4 (5) position.

The new compounds obtainable according to the invention have interesting physiological properties. They show a spasmolytic, vasodilatory effect, especially coronary dilatation Effect.

Of particular interest among these compounds are the following: 3a, 11j8-dihydroxy-20-methyl-20-dimethylamino-5 /? - pregnane and 3-oxo-20-methyl-20-dimethylamino-J ⁴ -pregnene.

Two particularly interesting representatives of this new class of compounds are also 3'- hydroxy-20-methyl-20-dimethylamino-5β-pregnane and 3a - (dimethylaminoacetoxy) - 20 - methyl - 20 - dimethylamino-5 /? - pregnane. These compounds have an excellent vasodilator, in particular coronary dilator, and spasmolytic action; administration of them in high doses gives no evidence of toxicity.

The useful dosage of these compounds is between 5 and 20 mg per dose and 10 to

mg per day in adults, depending on the route of administration.
The invention relates to a process for the preparation of compounds of the general formula I, using a primary amine of the formula NH ₂ R, in which R has the meaning given above, in a manner known per se, with one in the 3- and 11-positions accordingly substituted 20-oxo-5/3-pregnane or a corresponding 3/3-hydroxy-20-oxo / I ^B -pregnen converts, after previously the 3-keto function present in the steroid molecule by forming a cyclic ketal in a manner known per se has been protected, the resulting 20-imino derivative by treatment with a lower alkyl, aryl or aralkyl halide of the formula R ₁ -HaI (Hai means halogen, and R ₁ has the meaning given above) converted into the ternary iminium salt, this with an alkyl magnesium halide of the formula Hal-MgR ₂ (in which Hal is a halogen atom and R _{2 has} the meaning given above) converts the obtained

609 537/438

3 4

20-alkyl-20-aminosteroid by temporary salt- The compound is soluble in chloroform, in alcohol

Education cleans and any existing protected hol, acetone and benzene sparingly soluble and in water

3-keto function optionally free- insoluble by hydrolysis,

sets or the alcohol function in the 3-position of the _Al1Q i _{VC (1.} r w nxr vu «

ι ti ac t-> ι · ι i τ-> · ι t · analysis. \ ^ ν> Άν} Κ) Γ \ = JDl, JD.

obtained Δ ⁵ -Pregnenverbmdung with formation of a 5 _. ,, -, """" η, ^.,., ", - n, -κτ . ^ _nn ,

4 (5) double bond is oxidized or the ^Bf f <* « ^et · · · £ 79.70 · /“ H 11.25%, N 4.22%;

Hydroxyl group in the 3-position of the obtained 5 ^ -Pre- found ... L- / y, 8/0 ₎ H ll, u / ₀ , N 4.5 / ₀ .

The compound has been previously acylated and given in the literature

if the compound obtained is in a salt of an or- not described,

Ganic or mineral acid transferred. ok

In the case of the production of the above-mentioned B. Sa-Hydroxy ^ O-methylimino-Sß-pregnan-

upscale compounds one goes iodmethylat as follows
before:

For the production according to the invention of 3 ″ -hy- 20 g of 3 ″ -hydroxy-20-methylimino-5 /? - pregnane, hydroxy-20-methyl-20-dimethylamino-5/5-pregnane is introduced into 240 ml of chloroform, At normal, about 40 ml of the solvent is distilled off as starting compound 3a - hydroxy pressure, 20-oxo-5 /? - pregnane, this is added with methylamine in 60 ml of methyl iodide and converted for about 3 hours in the presence of sodium methylate, the reflux is kept . It is allowed to cool, the 3'-hydroxy-20-methylimino- 5ß -pregnant obtained for 30 minutes is cooled with ice, the precipitate formed is filtered off with suction, and by treatment with methyl iodide in the deswashed successively with chloroform and ether, speaking iodine methylate, leaves this dries with methyl and thus receives 27 g of crude iodine methylate from magnesium bromide react and thus receives the g3a-hydroxy-20-methylimino-5/3-pregnane. F. wanted Sw-Hydroxy ^ O-methyl ^ O-dimethylamino-305 ⁰ C (decomposition). The compound is sparingly soluble in 5/3-pregnane. in water and ethanol, in benzene and chloroform

For the production of 3a- (dimethylaminoacetoxy) - 25 insoluble.

20-methyl-20-dimethylamino-5/5-pregnan is used the analvse

3 ″ -hydroxy-20-methyl- _Ώ ΰ .., ₀ .

20-dimethylamino-5 _j e-pregnane with Ν, Ν-Dimethylgly- üerecünet ... J2ö, 8U / „;

cylchloridchlorhydrat um and isolate the desired getunden ... J 27.5 / ₀ .

Link. 30 The connection was previously still in the literature

For the preparation of 3 ", II / S-dihydroxy-20-methyl- not described.
20-dimethylamino-5 /? - pregnane is used as starting compound 3 (X-acetoxy-II _/ 5-hydroxy-20-oxo stage C. Soc-Hydroxy ^ O-methyWO-dimethyl-5 /? - pregnane and works analogously the amino-5 /? - pregnan described above
Preparation of Sa-Hydroxy ^ O-methyl ^ O-dimethyl- 35
amino-5 / i-pregnans. 140 ml of a 2.55 molar solution of methyl

To produce 3-oxo-20-methyl-20-dimethyl-magnesium bromide in ether, 180 ml of tetra-

amino-Zl ⁴ -pregnen is used 3 /? - Hydroxy-20-oxohydrofuran is introduced, then slowly 11.8 g

/ 4 ⁶ -pregnen as the starting compound, this converts 3 ″ -hydroxy-20-methylimino-5 /? - pregnaniodomethylate

analogous to the preparation of 3 ″ -hydroxy-20-methyl-40 added; the mixture is refluxed overnight and

20-dimethylamino-5 /? - pregnane in the 3 / J-Hydroxy- pour then slowly with stirring into the following

20-methyl-20-dimethylamino- / J ⁶ -pregnen, subject mixture to:

after that the aminosteroid obtained from the action of ice-water 1000 ml

of an oxidizing agent ζ B. Aluminum isopropylate Concentrated ammonia ". '.'. '.'. '.'. '. 150 ml

in the presence of Methyhsobutylketon, and get 45 ammonium chloride 100 g

by double exchange of functions the desired 3-oxo-20-methyl-20-dimethylamino- ^ l * -pre-

enjoy. Then extract with a mixture of

Benzene and ether (1: 1), one after the other washes the

For example 5 ° extracts with an ammonia-ammonium chloride mixture

Schung, with water and with salt water, dries over

Production of SÄ-Hydroxy ^ O-methyl ^ O-dimethyl- magnesium sulphate and evaporated to dryness. Of the

amino-5 / Ö-pregnane and its 3 «-dimethyl residue is dissolved with ethanol in the heat.

aminoacetylderivats are taken, then 20 ml of acetic acid and one

Stage A. 3 "-Hydroxy-20-methylimino-5 /? - pregnane 55 ^{solution of 12} ' ⁵ J sodium acetate in 20 ml of water.

set, the mixture is heated for 15 minutes

In a chilled to about -10 ⁰ C solution of 39 ml of nitrogen to about 8O ⁰ C and add 50 ml sodium hydroxide solution monomethylamine in 70 ml of methanol is brought to 13 g. The precipitate formed is then poured into an ice-water mixture, 3a-hydroxy-20-oxo-5 /? - pregnane and 3 g of sodium extracted with ether, methylate. 10 ml of methanol are added, the extracts are heated and the extracts are washed with water, dried and the reaction mixture is periodically evaporated to dryness overnight. The residue is dissolved in ether, stirring under pressure to 100 ⁰ C. It is then cooled passes into the solution a stream of gaseous mixture to about -10 ⁰ C., the gebilde- hydrochloric a suction filtered th crystals until an acid reaction, filtered with suction washed off the precipitate one after the other with methanol, dried and thus obtained 8.25 g and with water, dried and thus obtained 9.8 g of crude 65 crude 3 ″ -hydroxy-20-methyl-20-dimethylamino-3a-hydroxy-20 -methylimino-5 /? - pregnane, which by 5/5-pregnane chlorohydrate from F. about 29O ⁰ C.
Recrystallize from ethanol is purified. F. = 220 The hydrochloride obtained is dissolved in aqueous solution

up to 222 ⁰ C, [«] !? - + 58.5 ± 1 ° (c = 1 ° / ₀ , ethanol). Ethanol, then slowly add one with stirring

5 6

1 η-sodium hydroxide solution, then an ice-water-mi- The connection was still in the literature

Schung, sucks off the precipitate formed, not described.

washes with water, dries and thus receives the 3 «-Hy- The connection can easily be inserted into the corresponding

droxy-10-methyl ^ O-dimethylamino-Sβ-pregnane. Convert to dichlorohydrate:

Analysis, the product obtained is purified over the 5 1.26 g of the free amine with 15 ml of a

corresponding oxalate. 0.6N solution of dry hydrogen chloride in iso-

To this end, 5.49 g of this compound are dissolved in 55 ml of propanol. Then you suppress that

Ethanol, then adds a hot solution of isopropanol with stirring completely by adding benzene, separates the

of 3.3 g of oxalic acid in 28 ml of ethanol, the benzene mother liquor floating on top drains off,

Reaction mixture 10 minutes at temperature io dissolves the resinous residue in methanol, concentrated

the surroundings, then cool with ice for 30 minutes, the solution triturates and the crystals that have formed are filtered off with suction

sucks off the crystal precipitate that has formed, washes and dries it. This gives 1.4 g of crude 3 "- (dimen-

it with ethanol and with ether, dries and thus receives thylaminoacetoxy) - 20 - methyl - 20 - dimethylamino-

5.87 g of 3 ^ -hydroxy-20-methyl-20-dimethylamino-5 / 3- 5/3-pregnane dichlorohydrate, which is dissolved in methanol,

pregnane oxalate from F. = 255 to 256 ⁰ C. 15 The whole solution is then concentrated with addition

This compound is soluble in aqueous alcohol, from ethyl acetate to crystallization,

Slightly soluble in alcohols, in ether, acetone and F. = about 260 ⁰ C, [<x] l ° = +31.5 ± 1.5 ° (c = l%,

Benzene insoluble. Ethanol).

To get back the free base, one dissolves the product in water, dilute aqueous

5.87 g of the oxalate obtained in 50 ml of aqueous acids, alcohols and soluble in chloroform, little

Ethanol, add 6 ml of potassium hydroxide solution, diluted by insoluble in acetone, insoluble in ether and benzene,

set of water, extracted with ether, washes the α naive * · r w η xr ri - sio «

Extracts with water, dried over magnesium sulfate, ^J f ^ caha nmno «c« r * -to ««,

evaporates to dryness and thus receives 5.4 g of 3 * -Hy- Calculated ... C 64.74, H 10.08, N 5.39, C 13.6 "/";

hydroxy-20-methyl-20-dimethylamino-5 _i 5-pregnan from F. 25 Send ... C64.9, H 10.0, N5.2, Cl 13.5%.

about 54 ° C, [xfS = +21 + _ 1.5 ° (c = 0.7%, ethanol). The connection was previously still in the literature

The product is not described in the alcohols and in chloroform,
soluble, moderately soluble in ether and insoluble in water.

Analysis: C ₂₄ H ₄₃ ON = 361.59. B is ρ ie 1 2

Calculated ... C 79.72%, H 11.98 · /., N 3.87 · / .; ³ ° preparing 3 "ll / - dihydroxy-20-meth _y lgefunden ... C80,0%, H 12.0%, N4,2%. 20-dimethylamino-513-pregnane

The connection has been used in the literature so far “. . "" "". ^.,, "",,. .

not described ^{level A} 3 ", ll ^ dihydroxy-20-methyhmino-

₃₅ 5 ^ -pregnan

Preparation of 3 «-Dimethylaminoacetoxy- A solution of 250 ml of monomethyl-

20-methyl-20-dimethylamino-5β-pregnan amine in 300 ml of methanol at ⁰ ° C. and adds 43 g

3 "-Acetoxy-II / 3-hydroxy-20-oxo-5 /? - pregnane and 20 g

1.444 g of the 3'-hydroxy-20-me-sodium methylate obtained are dissolved. This reaction mixture will

thyl-20-dimethylamino-5 / chloroform cooled pregnane-3 in 28 ml of 40 overnight at 120 ⁰ C and stirred at ⁰ ° C;

form under a stream of nitrogen and cool in an ice bath. the precipitate is sucked off and filled with ice-cold

Then, while stirring, 3.160 g of Ν, Ν-dimethyl methanol and then washed with water and im

glycylchloride chlorohydrate, heated IV2 hours in vacuo, evaporated to dryness. You get so

Reflux, maintaining the nitrogen flow, 12.51 g of 3a, llj5-dihydroxy-20-methylimino-5/3-pregnane.

will. The solution obtained is allowed to cool and 45 The methanolic mother liquor gives at concentration

Then pour it into 150 ml of saturated sodium bicarbonate trituration an additional 11.97 g, so that a total of 24.48 g,

solution a. The organic phase is separated and obtained, corresponding to a yield of 62%,

the aqueous solution was re-extracted with chloroform. The F. = 234 ⁰ C, [*] ?? = +79.1 ± 1 ° (c - 1%, chloro-

combined chloroform solutions are with salt form).

water washed, dried and concentrated. __Man 50 The mother liquor of the second diluted with water

thus receives 2.3 g of an amorphous product, which in the amount of ether gives 13 g of 3a, ll /? - Dihydroxy-20-oxo-5 / J-pre-

is dissolved and filtered. The filtrate to dryness gnan mp = 209-210 ⁰ C.

evaporated. 1.7 g of crystallized 3a di-das 3 ", ll / ^ dihydroxy-20-methylimino-5 /? - pregnane are obtained in this way

methylaminoacetoxy - 20 - methyl - 20 - dimethylamino- results in the form of colorless crystals that are in alcohol

5 /? - pregnan. This becomes sparingly soluble by dissolving in 15 ml 55 and ether, soluble in chloroform and in

1 η-hydrochloric acid, washing the solution with ether and water are insoluble.

Make alkaline cleaned. The precipitate is analyzed with CHON = 347 53

Ether extracted, the ether solution washed, dried ^y ' ^{2a 3} ' .A '

net and evaporated. 1.5 g of 3 "-dimethyl- Calculated ... N 4.03 /";

aminoacetoxy-20-methyl-20-dimethylamino-5 / S-pregnan 60 found ... N 4.4 / ₀ .

in the form of a solid, colorless product, which is used in the The product was still in the literature

dilute aqueous acids, not described in ether and chloroform,
soluble and very sparingly soluble in water. F. = about

104 ⁰ C; [x] ² S = +40.5 + _ 1 ° (c = 1%, ethanol). grade B. Sa.ll / S-Dihydroxy ^ O-methylimino-

Analysis: C ₂₈ H ₅₀ O ₂ N ₂ = 446.70. ^6s 5 ^ -pregnan iodine methylate

Calculated ... N6.27%; 23.39 g of 3 ", 11S-dihydroxy-20-methyl-

found ... N 6.2%. imino-5 /? - pregnan in 300 ml of chloroform, distilled

7 8

30 ml of the solvent from, add 70 ml of methyl iodide then 50 g of 3/3-hydroxy-20-oxo-Zl ⁵ -pregnen and

to and heated 2 ¹ I for ₂ hours under a nitrogen atmosphere, 12 g of sodium methylate were added. Add 10 ml

to reflux. Methanol and heated the reaction mixture over

It is then cooled with ice, the precipitate off overnight with stirring and pressurized to 100 ⁰ C.

sucked, washed with chloroform and ether and at 5 Then it is cooled to -10 ° C, the formed

80 ° C dried in a drying cabinet. This gives crystals are suction filtered, with ice-cold methanol,

31.25 g Sajll / J-dihydroxy ^ O-methylimino-Sjö-pregnan-washed with aqueous methanol and with water

iodomethylate with a temperature of> 300 ° C, yield 95%. and dried. After recrystallization from methanol

The product is sparingly soluble in water and alcohol, 23 g of 3/3-hydroxy-20-methylimino- / I ^B -pre-

and in ether, acetone, benzene and chloroform un- io gnenvomF. = 230 ° C, [α] !? = -17.5 ± 2 ° (c = 0.5%,

soluble. Tetrahydrofuran). Yield = 44.2%.

Analvse · C H O NJ = 489 47 The product is obtained in the form of colorless crystals which

y 23 ίο ² '' slightly soluble in alcohol, acetone and chloroform and

Calculated ... J 25.93 J ₀ , N 2.86 J ₀ ; _in water, dilute acids and alkalis, ethers and

found ... J25.2 <> / ₀ , N2.6%. ₁₅ benzene are insoluble.

The product has so far been _analyzed in the literature: C ₂₂ H ₃₅ NO = 329.52.

not described. _. , ^ r, n «nm -rr« r. ^ * m ,,, .- «,

Calculated ... C80.19%, H 10.71%, N4.25%;

Grade C. S ^ lljff -dihydroxy ^ O-methyl ^ O-dimethyl- found ... C 80.1%, H 10.4%, N 4.2%.

amino-5 / S-pregnan _{ao The product} ^ _n J _{6 so far in the} literature

Bring 330 ml of a 3.42 molar solution of not described.
Methylmagnesium bromide in ether in 470 ml of tetrahydrofuran, slowly gives 31.25 g of the 3 ", 11 / Ö-Dihy-

Droxy-20-methylimino-5 ^ -pregnan-iodomethylats, the stage B. Production of 3 /? - Hydroxy-20-methyl-

was obtained above, and heated for 16 hours 25 imino-zJ ^B -pregnenjodmethylat
under a nitrogen atmosphere to reflux. Then pour

one in a mixture of 31 water, 300 g of ammonia 23 g of 3j8-hydroxy-20-methylimino-ZI ⁸ -pregnen werchlorid and 450 ml of concentrated ammonia. placed in 400 ml of chloroform. The mixture is then stirred for 30 to 40 minutes and extracted with a 40 ml of the solvent, distilled off, 80 ml of a methyl-benzene-ether mixture (1: 1). Then 30 iodide is added with water, and it is washed under reflux for 2 hours, dried over magnesium sulfate and heated in. It is then cooled with ice, and the precipitate is evaporated to dryness in vacuo. The product obtained in this way is filtered off with suction and treated with chloroform and ether is dissolved in 500 ml of ether and passed into the wash and dried. This gives 29.8 g of a crude solution of gaseous hydrogen chloride up to and including an acidic 3 /? - hydroxy-20-methylimino-zl ^B- pregnene-iodomethylate reaction. The mixture is stirred for 30 minutes, suction filtered and the mp = 280 ° C with decomposition, yield 90.5%, are first 250 ml of aqueous ethanol and then 500 ml, which is used directly for further reaction. Water is added and the mixture is left under stick for 1 hour. The product is obtained in the form of white crystals which are in the substance atmosphere at room temperature. Alcohol and benzene are sparingly soluble and in water,

One washes with ether and with petroleum ether and gives thin acids and alkalis, ether, acetone and

40 ml of sodium hydroxide solution to it. The precipitate formed is insoluble in chloroform,

is suction filtered and the aqueous solution with a »„ „ι ™ ,,, ρ pr τχτπ - 471 47

Benzene-ether mixture (1: 1) extracted. _n ^J , f ^dS _, _ _o ' _T '. _T "," _ _XT " _nnnl

19.18 g of crude 3 ^, 11 / J-dihydroxy- "n" C '' Ss'o J27 0 'N ^ are obtained in this way

20-methyl-20-dimethylamino-5iS-pregnane. Found ... C 58.3, H 8.0, J 27.0, N 2.6 / ₀ .

The product obtained by recrystallization from isopropyl ether has hitherto been found in the literature

Purified product has the following constants: F. = about not described.
150 ° C, [K] ¹ S = +39.5 ± 1 ° (c = 1%, ethanol).

The product is obtained in the form of colorless crystals, grade C. SiS-Hydroxy ^ O-methyl ^ O-dimethyl-

in alcohol, ether, acetone, benzene and chloroform amino- / l ⁵ -pregnen
are soluble. 50

₄ "", " ₀₀ . _r ti n _M IT? cn 280 ml of a 3.2 molar solution of methyl mag-

/ \ naiyse. v ^ o4tij ₃ u ₂ iN = j //, Dy. , ., . t. ,,. _Ληη , _,. ,,

L _ _Λ _, _{0 /} υ _ΛΛ . "", .Γ -j -7-, 0 / sium bromide m ether become m 400ml tetrahydro-

calculated ... C76, i4 / ₀ , H 11.4 / J ₀ , is \ ά, / LJ ₀ ; _{furan ei nge} forward, then slowly 28,8g be the

found ... C 76.5 / ₀ , H 11.3 J ₀ , N 3.9 I ₀ . added product obtained above and the

The product was previously in the literature 55 reaction mixture overnight under nitrogen atmosphere

not described. Sphere heated to reflux. Then you pour them in

By treating a solution of the product in a mixture of 2400 ml ice-water, 240 g am-

Ethyl acetate with 1,45N hydrogen chloride in monochloride and 320 ml of concentrated ammonia.

Ether, the hydrate of chlorine is obtained from F. = about. The product obtained is filtered and washed with it

300 ° C. 60 water and first gives 25 ml of methanol and then 52 ml

. . Acetic acid and 52 g sodium acetate, dissolved in 60 ml

B e ι s ρ 1 e 1 3 water, added and heated for 1 hour to 80 ° C. Then bring

Production of 3-oxo-20-methyl-20-dimethyl- one by adding sodium hydroxide solution to pH 10, pours

amino- ^ l ⁴ -pregnen then in 2400 ml of water and cool for 1 hour

nx * λ -.η ττ λ _nn 1,. · Λ κ ⁶ 5 with ice. The precipitate formed is washed with water

Stage A. 3 ^ Hydroxy-20-methyhmmo-Zf ^B _-pregnen washed, extracted with ether, over magnesium

A solution of 200 ml of monomethylamine dried in sulfate, poured over animal charcoal, filtered and

240 ml of methanol are cooled to -10 ° C. and saturated with gaseous hydrogen chloride.

One obtains 15.813 g of crude 3 /? - hydroxy-20-methyl-20-dimethylamino-zl ⁵ -pregnen chlorohydrate, mp = 245-250 ⁰ C, which is dissolved in 180 ml of methanol, and sodium hydroxide to pH 8 to 9 brings.

If one adds 400 ml of methanol, concentrated, cooled with ice, filtered off under suction, washed, dried in a drying oven and thus obtains 12.685 g of 3.beta.-hydroxy-20-methyl-20-dimethylamino-J ⁸ -pregnen mp = 17O ⁰ C , [<x] l ° = -65 ± 1 ° (c = 1%, tetrahydrofuran). The yield is 57.5%.

The product is obtained in the form of colorless crystals in dilute acids, ethers, benzene and chloroform are sparingly soluble and insoluble in water, dilute alkalis and acetone.

Analysis: C ₂₄ H ₄₁ NO = 359.58.

Calculated ... C 80.15 ° / ₀ , H 11.49%, N 3.9%;
found ... C 80.4%, H 11.2%, N 4.3%.

The product has not yet been described in the literature.

Stage D. S-Oxo ^ O-methyWO-dimethylamino-J ⁴ -pregnen

A mixture of 5 g of 3/3-hydroxy-20-methyl-20-dimethylamino-J ⁵ -pregnen, 50 ml of methyl isobutyl ketone and 2 g of aluminum isopropoxide is heated to reflux, then 100 ml of methyl isobutyl ketone are slowly added. 85 ml of solvent are distilled off, 25 ml of water are added and the methyl isobutyl ketone is driven off. It is then extracted with methylene chloride, poured over animal charcoal, filtered, washed and evaporated to dryness in vacuo. After crystallization from methanol to obtain 2.46 g of 3-oxo-20-methyl-20-dimethylamino-J ⁴ -pregnen mp = 209-210 ⁰ C, [x] l ⁰ = +57 ± Γ (c = 1 %, tetrahydrofuran). The yield is 49.2%.

The product is obtained in the form of crystals, which are soluble in chloroform, in dilute acids, alcohol and ethers are sparingly soluble and insoluble in water and dilute alkalis.

Analysis: C ₂₄ H ₃₉ NO = 357.56.
Calculated ... C 80.61%, H 10.99%, N 3.92%; found ... C 80.7%, H 10.7%, N 3.9%.

The product has not yet been described in the literature.

45

Claims (5)

Patent claims: 1. Process for the preparation of 20-tert-amino-20-alkyl steroids the general formula 55 CH ₃ -C- N: 65 wherein R and R _{1 are} lower alkyl, aryl or aralkyl radicals, R _{2 is} an alkyl radical having 1 to 4 carbon atoms, X is an oxygen atom or the grouping "OR ₃ R _{s is} a hydrogen atom or a substituted or unsubstituted lower acyl radical and YH ₂ or means, whereby these compounds are either saturated and then belong to the 5 / S-pregnane series or, if X is an oxygen atom, can contain a 4 (5) double bond, as well as salts of these compounds, characterized in that in per se as is known, a primary amine of the formula NH ₂ R, in which R has the meaning given above, with a 20-oxo-5 /? - pregnane correspondingly substituted in the 3- and 11-positions or a corresponding 3 / I-hydroxy-20 -oxo-z! ⁵ -pregnen, after previously protecting the 3-keto function present in the steroid molecule by forming a cyclic ketal in a manner known per se, the 20-imino derivative obtained by treatment with a lower alkyl, aryl or aralkyl halide of the formula Hai - R ₁ (in which Hai is a halogen atom and R _{1 has} the meaning given above) converted into the ternary iminium salt, which reacts this with an alkyl magnesium halide of the formula Hai - MgR ₂ (in which Hai is a halogen atom and R _{2 has} the meaning given above), which The 20-alkyl-20-tert-aminosteroid obtained is purified by temporary salt formation and any protected 3-keto function that may be present is liberated by hydrolysis or the alcohol function in the 3-position of the Δ ⁵ -pregnene compound obtained to form a 4 (5) position The double bond is oxidized or the hydroxyl group in the 3-position of the 5/3 pregnane compound obtained is optionally acylated and optionally The compound obtained is converted into a salt of a mineral acid or an organic acid. 2. Process for the preparation of 3 * -hydroxy-20-methyl-20-dimethylamino-5jS-pregnane according to claim 1, characterized in that the 3 "-hydroxy-20-oxo-5 / S-pregnane is used as the starting compound, this reacts with methylamine in the presence of sodium methylate, the Ζ »- hydroxy - 20 - methylimino -5 / 3-pregnane formed is converted into the corresponding iodine methylate by treatment with methyl iodide and the iminium salt obtained is reacted with methyl magnesium bromide. 3. Process for the preparation of 3 "- (dimethylaminoacetoxy) - 20 - methyl - 20 - dimethylamino-5/5-pregnane or its dichlorohydrate according to claim 1, characterized in that the 3a-hydroxy obtained according to claim 1 or 2 20 - methyl - 20 - dimethylamino -5ß- pregnane is reacted with N ^ -dimethylglycyl chloride chlorohydrate, the desired 3 "- (dimethylaminoacetoxy) -20-methyl-20-dimethylamino-5 /? - pregnane is isolated and 609 537/438 if necessary with a solution of dry hydrogen chloride in isopropanol in the appropriate Dichlorohydrate transferred. 4. A process for the preparation of 3 ", ll /? - dihydroxy - 20 - methyl - 20 - dimethylamino - 5ß - pregnane according to claim 1, characterized in that the starting compound Sa-acetoxy-lljÖ-hydroxy-20-oxo-5 / 9-pregnan used and according to claim 2 works. 5. Process for the preparation of 3-oxo-20-methyl-20-dimethylamino-z) ⁴ -pregnen according to Claim 1, characterized in that the starting compound used is 3/3-hydroxy-20-oxo- / d ⁵ -pregnen, this according to claim 2 in the 3/3-hydroxy-20-methyl-20-dimethylamino-J ⁵ - pregnen transferred and the latter compound subjected to the action of an oxidizing agent, in particular aluminum isopropylate in the presence of methyl isobutyl ketone. Considered publications:
U.S. Patent No. 3,013,008. 60? 537/438 3.66 © Bundesdruckerei Berlin