DE1245375B - Process for the preparation of 6alpha-amino-4-pregnen-3, 20-dione or its N-acylates - Google Patents

Description

Federal Republic of Germany

GERMAN

PATENT OFFICE

EDITORIAL

Int. Cl .:

C07C c o7j

German class: 12 ο -25/05

Number: 1245 375

File number: S86136IVb / 12o

Filing date: July 12, 1963

Opened on: July 27, 1967

The present invention relates to a process for the preparation of 6a-amino-4-pregnen-3,20-dione or its N-acylates, which are represented by the structural formula

NHR '5

can be illustrated in which formula R is a hydrogen atom or a lower alkanoyl group, z. B. acetyl, propionyl, butyryl or valeryl. These compounds are physiologically active. They are made from 5a-hydroxy-6 / i-aminopregnan-3,20-dione and its N-acylates or their 3,20-bisethylene ketal derivatives (H) and 6β-amino-4-pregnen-3,20-dione and its N-acylates (III) prepared according to the following reaction scheme:

CH ₃
C = X

HO I

NHR

or

(IU)

NHR process for the production of 6 "" amino-4-pregnen-3,20-dione or its N-acylates

Applicant:

Shionogi & Co. Ltd., Osaka (Japan)

Representative:

Dr. H. Wittek, patent attorney, Heidelberg-Schlierbach, Im Grund

Named inventor: Kanzo Sasaki, Osaka (Japan)

Claimed priority:

Japan July 17, 1962 (30 498)

in which R has the abovementioned meaning and X is an oxygen atom or the ethyl ketal radical.

7MCW5S1

The 5a-hydroxy-6jS-aminopregnan-3,20-dione and its N-acylates or their 3,20-bisethylene ketal derivatives (II) and 6jS-amino-4-pregnen-3,20-dione and its N- Acylates (III) are new and can be prepared from 5a, 6a-epoxypregnane-3,20-dione-3,20-bisethylene ketal (Bowers and coworkers, Tetrahedron, 7, p. 138 [1959]) in such a way that one the latter to a temperature of 80 to 15O ⁰ C, is reacted in a sealed tube and the 5 'obtained -hydroxy-6 -azidopregnan with sodium azide in an inert solvent such as methanol, ethanol, ether, tetrahydrofuran or dioxane, at ^ - 3 , 20-dione - 3,20-bisäthylenenketal with lithium aluminum hydride in an inert organic solvent such as benzene, ether, tetrahydrofuran or dioxane, at a temperature of room temperature, that is from 15 to 30 ° C, and reduced to the boiling point of the solvent used then, if necessary, decentralized and / or acylated and / or dehydrated in the usual way. Protection is not sought for the production of the starting materials in the context of the present invention.

According to the present process according to the invention, the 5α-hydroxy-6 /? - aminopregnan-3,20-dione and its N-acylates or their 3,20-bisethylene ketal derivatives (II) and 6 /? - amino-4-pregnen used as starting material -3,20-dione and its N-acylates (III) treated in a manner known per se with an acid, the starting material (II) being dehydrated and isomerized at the same time and the corresponding 60-amine (I) being obtained, or the starting material ( III) is isomerized and the corresponding 6a-amine (I) is obtained. A customary organic and inorganic acid, such as hydrochloric, sulfuric, acetic or p-toluenesulfonic acid, can be used as the acid. The reaction proceeds easily by treating the starting material (II) or (III) with the appropriate acid in a wide temperature range, for example from -20 to 100 ^° C., preferably with cooling with ice, if necessary in the presence of an inert solvent such as Ether, dioxane, acetone, benzene or acetic acid.

In general, the free amine product (I, R-H) is relatively unstable and difficult to purify. But it can be acylated in the usual way, for. B. by treatment with a mixture of a lower alkanecarboxylic anhydride and pyridine, the corresponding N-acylates (I, R = acyl) are obtained, which are more stable and can be more easily purified in the usual way by extraction and crystallization.

The compounds produced according to the process of the invention are used as sedatives for the central nervous system useful. For example, it causes 6a-acetylamino-4-pregnen-3,20-dione observed anesthetic condition for 6 to 8 hours in mice weighing approximately 16 g Administration of a dose of 0.3 mg per mouse by the intraperioneal route.

example 1

Dry hydrogen chloride was bubbled through a solution of 240 mg of 5a-hydroxy-6 ^ -aminopregnane-3,20-dione-p-toluenesulfonic acid salt in 8 ml of glacial acetic acid for 40 minutes. The reaction mixture was then added to an aqueous solution of sodium hydroxide. The mixture obtained is saturated with sodium chloride and shaken with dichloromethane. The dichloromethane phase is then shaken with 5% hydrochloric acid and the hydrochloric acid phase made alkaline with sodium hydroxide, saturated with sodium chloride and extracted with dichloromethane. The dicblomethane extract is then washed with water, dried over anhydrous sodium sulfate and evaporated; 54 mg of 6a-amino-4-pregnen-3,20-dione are obtained as yellow crystals with a melting point of 140 ° to 148 ° C. (decomposition). IR: ν ££ "'= 3388, 3308, 1703, 1660, 1610 cm- ^1. UV: λ ^" ^{ο {} = 240 πΐμ (ε = 12 400).

5a-Oxy-6 /? - aminopregnan-3,20-dione is applied to the allowed to react as described above, whereby 6a-amino-4-pregnen-3,20-dione is obtained.

6a-Amino-4-pregnen-3,20-dione is acetylated with acetic anhydride in pyridine at room temperature, that is at 15 to 30 ° C, resulting in 6a-acetylamino-4-pregnen-3,20-dione in the form of Leads to crystals with m.p. = 122 to 124 ° C; [a] f - = + 118 ± 2 ° (c, 0.996 in chloroform). UV: λ ä «. ·» »» » ¹ = - 240 ηψ (ί = 13 700). IR: * chloroform ^ ₃₄₃₆₎ 33 _26>J703;

1675, 1664, 1621, 1513, 1506, 1361cm- ¹ .
Analysis for C23H33O3N:

Calculated ... C 74.36, H 8.75, N 3.77;

found ... C 74.39, H 9.00, N 3.58.

Example 2

Dry hydrogen chloride is passed through a solution of 43 mg of 5a-hydroxy-6 /? - acerylaminopregnan-3,20-dione in 2 ml of glacial acetic acid for 30 minutes while cooling with ice and then left to stand for 2 hours, also under ice bucket. The reaction mixture is then mixed with 2 ml of water and the resulting mixture is shaken with dichloromethane. The dichloromethane phase is washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue is crystallized from ether and recrystallized from a mixture of acetone and ether, and delivers 23 mg of 6a-acetylamino-4-pregnene-3,20-dione, mp = 122 to 124 ⁰ C; [α]! "= + 118 ± 2 ° (c, 0.996 in chloroform), UV: ^ i?" ⁰ '= 240 ηΐμ (ε = 13,700); IR: v ™ ° ^rororm = 3436, 3326, 1703, 1675, .. 1664, 1621, 1513, 1506, 1361 cm " ¹ .

Example 3

Dry hydrogen chloride is passed through a solution of 1.05 g of 5a-hydroxy-6 /? -Acetylaminopregnane-3.20-dione-3.20-bisethylene ketal in 20 ml of glacial acetic acid for 45 minutes while cooling with ice. The reaction mixture is combined with water, saturated with sodium chloride and shaken with chloroform. The chloroform phase is then washed with 5% sodium carbonate and then with water, dried over anhydrous sodium sulphate and evaporated under reduced pressure. The oily residue is crystallized from a mixture of acetone and ether, and provides 513 mg of 6-acetylamino-4-pregnene-3,20-dione in the form of crystals with mp = .122 to 124 ⁰ C.

Example 4

To a solution of 80 mg of 5a-hydroxy-6/3-acetylaminopregnane - 3.20 - dione - 3.20 - bisethylene ketal in

90 mg of p-toluenesulfonic acid are added to a mixture of 2 ml of acetone and 1 ml of dioxane, and the reaction mixture is ^{stirred at room temperature, that is at 15 to 30 °} C., for 17 hours. Thereafter, that is the Sa-hydroxy-o / J-acetylaminopregnan-3,20-dione containing mixture heated at 70 ⁰ C for 10 minutes, whereby a clear solution is obtained. After stirring at the same temperature for 3 hours, water is added. The resulting mixture is then shaken with chloroform and the chloroform phase washed with 5% sodium carbonate solution and then with water and evaporated. The residue is crystallized from a mixture of acetone and ether and yields 35 mg of oa-acetylamino - ^ - pregnen-3,20-dione in crystals with a temperature of 122 to 124 ° C.

Example 5

With a solution of 50 mg of 6ß-acetylamino-4-pregnen-3,20-dione dry hydrogen chloride is dissolved in 1.5 ml of glacial acetic acid for 40 minutes while cooling with ice directed. The reaction mixture is mixed with water and saturated with sodium chloride and shaken with chloroform. The chloroform phase is then mixed with 5% sodium carbonate solution

CH ₃

C = X

or and then washed with water and evaporated. The oily residue is made from a mixture of Acetone and ether crystallize and provide 40 mg of 6a-acetylamino-4-pregnen-3,20-dione in the form of Crystals with m.p. = 120 to 124 ° C.

Claims (1)

Claim: Process for the preparation of 6a-amino-4-pregnen-3,20-dione or its N-acylates of the general formula C = O NHR wherein R is a hydrogen atom or a lower alkanoyl group, characterized in that that one is a compound of the general formula CH ₃ O = NHR NHR wherein R has the same meaning as above and X is an oxygen atom or the ethylene ketal radical, in Reacts with an acid in a manner known per se and optionally also in a manner known per se Acylated way. References considered: U.S. Patent No. 2,985,650.