CH368161A - Process for the preparation of 11-amino steroids - Google Patents

Description

  

  



  Process for the preparation of 11-amino steroids
It has been found that 11-aminosteroids can be obtained if 11-keto-steroids are oximated and the 11-oximes obtained are reduced.



   The 11-amino steroids obtained are new and are characterized by interesting biological effects; they can also be used as intermediates for the preparation of other biologically active compounds.



   For the oximation one uses hydroxylamine or its salts, z. B. the hydrochloride or acetate. The reaction is advantageously carried out at an elevated temperature, in particular in boiling tetrahydrofuran or dioxane. Depending on the starting material used, it takes about 1 to 14 days to complete the reaction. The 11-oximino steroids obtained are readily crystallizing, mostly sparingly soluble compounds and can be crystallized from suitable solvents, e.g. B. acetone, ethyl acetate, methylene chloride and chloroform, clean.



   A number of methods are available for the reduction of the 11-oximino to the 11-amino group. So you can reduce by means of catalytically excited hydrogen, z. B. hydrogen in the presence of a platinum catalyst in glacial acetic acid solution, using nascent hydrogen, z. B. sodium or lithium in the presence of an alcohol, or by means of suitable light metal hydrides, e.g. B.



  Lithium aluminum hydride. In the catalytic hydrogenation and reduction with lithium aluminum hydride, the 11-amino-steroids are mainly obtained. The reduction using sodium and alcohol, e.g. B. Isopropanol, on the other hand, supplies the predominant quantities of the IIIa-amino steroids.



   The 11-amino steroids obtained can be converted into their acid addition salts in a known manner, e.g. B.



  Hydrohalides, chlorates, perchlorates, tartrates, etc., transfer. These salts are suitable for the preparation of aqueous solutions. If the 11-amino steroids formed still contain ketalized oxo groups, e.g. B. in the 20 position, this can be done in a known manner, for. B. by means of acid hydrolysis, converted into free oxo groups.



   Suitable starting materials for the present method are 11-keto-steroids, which are from the known steroid series, such as the Cholestan-, Ergostan-, Sitostan-, Spirostan-, Cholan-, Bisnorcholan-, Atiocholan-, Pregnan- and Allopregnan- , Androstane and ostran series, or of tetracyclic triterpenes (4,4,14-trimethyl steroids), e.g. B. from lanosterol. In addition to the 11-keto group, the starting materials can have any further substituents, such as free or esterified or etherified hydroxyl groups or ketalized or enolized oxo groups and alkyl, e.g. B. methyl groups.



  These substituents are particularly present in the 1, 2, 3, 4, 6, 9, 12, 17, 20 and 21 positions.



  The starting materials can be saturated in the ring system or have double bonds, for example in one or more of the positions 1, 4, 5, 14, 16 and 17, 20. The starting materials are known or can be obtained by methods known per se.



   In the examples below, the temperatures are given in degrees Celsius.



   Example 1 1 g of 11-ketotigogenin, 10 g of hydroxylamine hydrochloride, 40 cm3 of pyridine and 80 cm3 of abs. Ethanol are refluxed for 1 week. The solution is then evaporated to dryness under reduced pressure, the residue is suspended in water, filtered off and washed with water until the filtrate reacts neutral. 1.1 g of a crude product are obtained, which is recrystallized from ethyl acetate-heptane, 0.35 g of 11-oximino-tigogenin having a melting point of 273-275 (with decomposition). IR spectrum: bands at 2.86 and 3.00, u (hydroxyl) and 6.07 (oxime).



   A solution of 5 g of 11-oximino-tigogenin in 400 cm3 of tetrahydrofuran is added dropwise to a solution of 10 g of lithium aluminum hydride in 500 cm3 of tetrahydrofuran and the mixture is boiled for 5 days while stirring in a nitrogen atmosphere. After cooling, water is carefully added dropwise to decompose the excess lithium aluminum hydride, the reaction solution is made acidic to Congo with hydrochloric acid and extracted with methylene chloride-ether. After evaporation, this extract provides 2.16 g of neutral. By alkalizing the above hydrochloric acid solution, 1.64 g of crude 11-amino-tigogenin are obtained, which can be separated by chromatography on aluminum oxide and crystallization from methanol.



  The IIss-amino-tigogenin melts at 182-183, [a] 27 = -560, the isomeric IIIa-amino-tigogenin at 200-203, [a] 217 = -39. Both isomers yield crystallized hydrochlorides.



   Example 2
1 g of 3-acetoxy-11-keto-20-ethylenedioxy-ailo-pregnane, 10 g of hydroxylamine hydrochloride, 10 g of sodium hydroxide and 150 cm3 of abs. Ethanol are refluxed for 20 hours. The mixture is then evaporated to dryness, first under atmospheric and later under reduced pressure. The residue is stirred with water, filtered off on a glass suction filter and washed with water until the filtrate reacts neutral. The dried 34-hydroxy-l-oximino-20-ethylenedioxy-allopregnane obtained in this way (0.86 g) is crystallized from dioxane ligroin and gives 0.75 g (80n / a) of fine crystals which are below 300, decompose without melting.

   IR spectrum: bands at 2.93 and 3.00, u (hydroxyl), 6.08 u (oxime).



   A solution of 0.5 g of 3,6-hydroxy-ll-oximino-20-ethylenedioxy-allopregnane in 50 cm3 of tetrahydrofuran is added to a solution of 1 g of lithium aluminum hydride in 50 cm3 of tetrahydrofuran and the mixture is boiled for 6 days in a nitrogen atmosphere. After working up according to Example 1, in addition to neutral components, 0.2 g of 3jB-hydroxy-II, e-amino-20-ethylenedioxy-allopregnane is obtained, which is dissolved in 30 cm3 of acetone for the purpose of ketal cleavage and after addition of 20 mg of p-toluenesulfonic acid for 14 hours is allowed to stand at room temperature.

   After evaporation of the reaction solution alkalized with sodium bicarbonate, 3fl-hydroxy-Ilfl-amino-20-keto-allopregnane is obtained, which, after recrystallization from methylene chloride-ether, melts at 191-195. The preparation is water-soluble in the form of its salts.



   Example 3
500 mg 3jss-hydroxy-II-keto-lanostane, 4 g hydroxylamine hydrochloride, 20 cm3 pyridine and 40 cm3 abs. Ethanol are refluxed for 14 days. The solution is then concentrated to dryness under reduced pressure, the residue is taken up in ether and washed several times with water, the wash water being re-extracted twice with ether each time. After working up, 510 mg of crude 3ss-hydroxy-ll-oximino-lanostane are obtained. This is recrystallized from methylene chloride, methanol, mp 211-213. IR spectrum: bands at 2.79 and 2.95 (hydroxyl), 6.07 a (oxime) (Nujol).



   By reducing the 3ss-hydroxy-ll-oximino-lanostane according to the information in Example 1, the 3ss-hydroxy-ll-amino-lanostane is obtained.



   Example 4
A solution of 1 g of 3ss-acetoxy-11, 20-diketo allopregnan and 10 g of hydroxylamine hydrochloride in 40 cm3 of pyridine and 80 cm3 of abs. Ethanol is refluxed for 6 days. The solution is then evaporated to dryness under reduced pressure, the residue is suspended in water, filtered off and washed with water until the filtrate reacts neutral. The crude 3ss-acetoxy-11, 20-dioximino-allopregnane filtered off in this way is recrystallized from methylene chloride-methanol, yield: 0.54 g, melting point 249-253. IR spectrum: bands at 3.07 ti (oxime-OH), 5.80 and 8.03 a (acetate), 6.06, u (oxime).



   By reducing the 11,20-dioxime obtained analogously to the information in Example 1, 3ss-hydroxy-11,20-diamino-allopregnane is obtained.

 

Claims (1)

PATENT CLAIM Process for the production of 11-amino steroids, characterized in that an 11-keto steroid is reacted with hydroxylamine or a salt thereof and the oxime obtained is reduced. SUBCLAIMS 1. The method according to claim, characterized in that the oximation is carried out in boiling tetrahydrofuran or dioxane. 2. The method according to claim, characterized in that the 11-oximes by means of catalytically excited or nascent hydrogen or by means of light metal hydrides, for. B. lithium aluminum hydride, reduced. 3. The method according to claim, characterized in that 11-amino-steroids obtained are converted into their acid addition salts.