DD235649C2 - PROCESS FOR PREPARING 17BETA-AMINO-5BETA, 14BETA-ANDROSTAN-14-OLENE - Google Patents

Description

II

wherein R 'is a hydrogen atom or a hydroxy group, R ^{2 is} a hydrogen atom or an acyloxy group, R ^{3 is} a hydrogen atom or an acyloxy group, R ^{4 is} a methyl, Acyloxymethyl- or an optionally protected aldehyde group and R ^{5 is} an acyl radical or an acylated mono- or Oligosaccharidrest, preferably a tetra-O-acetyl-tri-D-digitoxosylrest, oxidized with selenium dioxide in boiling dioxane to 17a hydroxy compound, then the lactone ring at room temperature oxidatively degraded with potassium permanganate in acetone, the obtained 17-ketone with sodium borohydride in aqueous Ethanol at room temperature to 17o-hydroxy compound, this as 17 <* - TosylatrnitSodium azidine dimethylformamide at 150-160 ⁰ C to 17j8-azide, the 17/3 azide with lithium aluminum hydride in anhydrous tetrahydrofuran in an inert gas atmosphere, for example in a nitrogen or Argon atmosphere, reduced at room temperature to the target compounds I and simultaneously desacylated t and the resulting intermediates and target compounds, if necessary, according to known methods, such as distribution, chromatography and / or recrystallization, purified.

Field of application of the invention

The invention relates to a process for the preparation of 17/3 amino-5 / 3,14 / 3-androstane-14-ols of general formula I.

R ⁵ O

wherein R ^{1 is a} hydrogen atom or a hydroxy group, R ^{2 is} a hydrogen atom or a hydroxy group, R is a hydrogen atom or a hydroxy group, R ^{4 is} a methyl, hydroxymethyl or aldehyde group and R ^{5 is} a hydrogen atom or a mono- or oligosaccharide residue in glycosidic bond , The invention can find application in the pharmaceutical industry.

Characteristic of the known technical solutions

The 17a-hydroxylation of 17/3 cardenolides used for the preparation of the target compounds I in the first step was reported by N. Danieli et al. Danieli, Y. Mazur, F. Sondheimer, T., 23, 715-720, 1967). 17a-amino-5a-androstane derivatives have been reported by M. Davis et al. Davis, E.W. Parnell, D. Warburton, J. Chem. Soc. (C) 1698-1700, 1966) from 3/3-acetoxy-17/3-tosyloxy-5a-androstane via the 17e-azide.

Compounds of formula I with the typical for herpes steroids A / B cis and C / D-cis linkage are not yet known.

Object of the invention

The object of the invention is the development of a generally applicable process for the preparation of 17/3 amino-5 / 3,140-androstan-14-ols I from the naturally occurring 5 / 3,14 / 3-card-20 (22) -enolides and their glycosides.

Explanation of the essence of the invention

According to the invention, 170-amino-5,3,14i3-androstane-14-o (e of the general formula I are prepared by reacting, in a manner known per se, a corresponding Card-20 (22) -enolide or a corresponding Card-20 (FIG. 22) -enolidglycoside of the general formula II

wherein R ^{1 is} a hydrogen atom or a hydroxy group, R ^{2 is} a hydrogen atom or an acyloxy group, R ^{3 is} a hydrogen atom or an acyloxy group, R ^{4 is} a methyl, acyloxymethyl or an optionally protected aldehyde group and R ^{5 is} an acyl radical or an acylated mono- or Oligosaccharidrest, preferably a tetra-O-acetyl-tri-D-digitoxosylrest, oxidized with selenium dioxide in boiling dioxane to the 17a-hydroxy compound, then the lactone ring oxidatively degraded at room temperature with potassium permanganate in acetone, the resulting 17-ketone with sodium bromide in aqueous Ethanol at room temperature to 17a-hydroxy compound, this as 17a-tosylate with sodium azide in dimethylformamide at 150-160 ⁰ C to 17/3-azide and the 17ß-azide with lithium aluminum hydride in anhydrous tetrahydrofuran in an inert gas atmosphere, for example in a nitrogen or argon atmosphere, reduced at room temperature to the target compounds I and at the same time acylated. The resulting intermediates and the target compounds are optionally purified by methods known per se, such as distribution, chromatography and / or recrystallization. The manufacturability of the 17/3 amino-50,14 / 3-androstan-14-ols by the process according to the invention is surprising, since the formation of 17/3 substituted 5/3,140 steroids is much less favored thermodynamically than that of the corresponding 17asubstituted Steroids with the same ring linkage.

In the molecular biological value determination with the coupled optical test in equilibrium (W. Schoner, C. von Ilberg, R. Kramer and W. Seubert, European J. Biochem., 1,334-343,1967), the 3/3-tri-D- digitoxo-yloxy-170-amino-5 (3, -14β-androstane-14-ol (I, R ¹ R ³ = H, R ⁴ = CH ₃ , R ⁵ = tri-D-digitoxosyl) an inhibition of Na, K-dependent adenosine triphosphate phosphohydrolase of the human brain, which correlates with a positive inotropic effect on the deficient heart The method according to the invention will be explained in more detail below using an exemplary embodiment without being restricted thereby.

embodiment

3 / 3- (3 ', 3 ", 3"' _/ 4 '"- tetra-O-acetyl-tri-D-digitoxosyloxy) -14,17a-dihydroxy-5ft 14/3-card-20 (22) - enolide (III) A solution of 5.5 g of 3 / 3- (3 ', 3 ", 3'' _/ 4''- tetra-O-acetyl-tri-D-digitoxosyloxy) -14-hydroxy-5β, 14 / 3-card-20 (22) -enolide (digitoxin-3 ', 3 ", 3'", 4 "'- tetraacetate, II, R 1, R ³ = H, R ⁴ = CH ₃ , R ⁵ = tetraacetate). tri-O-acetyl-D-digitoxosylrest; 5,9x10 ^'3 moles) in 670 ml of dioxane with 3,44g of freshly sublimed selenium dioxide (3;. ix 10 ^-2 moles) were heated under reflux for 10 hours, the reaction mixture is after Abfilitrieren evaporated from excess selenium hydroxide and precipitated metallic selenium in vacuo

is extracted with chloroform, the chloroform extract washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated i. turned dampens. The column chromatographic purification on 300 g of silica gel 60 (particle size 0.063-0.200 mm, Merck; filling height: 28.5 cm) with chloroform-ethanol 98: 2 as eluent provides 4.3 g (77% of theory) of chromatographically pure 3 # - (3 ', 3 ", 3'", 4 '"- tetra-0-acetyl-tri-D-digitoxoxyloxy) -14,17a-dihydroxy-5 / 3,14 / 3-card-20 (22) -enolide (17a -Hydroxydigitoxin-3 ', 3 ", 3'", 4 ' "- (tetraacetate) lll).

[afo + 46 ° (C = 2.23; EtOH) UV: X _max 216 nm (e = 13100)

3 (3- (3 ', 3 ", 3''', 4 '''- tetra-O-acetyl-tri-D-digitoxosyloxy) -14-hydroxy-5 / 3,14 /? -Androstane-17-one ( IV) 4g III (4,2x10 ~ ³ moles) is - dissolved in 175 ml acetone -. portionwise (at room temperature with potassium permanganate 6,55g 4,2 χ 10 ~ ² moles) was added one hour after the start of the addition, the reaction mixture is worked up The acetone is stripped off after addition of 1 g of sodium bisulfite in vacuo and the solid residue is extracted several times with hot chloroform and then with chloroform from room temperature, the chloroform extract is washed with water, dried with sodium sulfate and concentrated by evaporation in vacuo. 3 ", 3 '", 4''' - tetra-0-acetyl-tri-D-digitoxosyloxy) -14-hydroxy-5i3,14i3-androstan-17-one (IV) remains as a colorless solidified foam.

Yield: 1.4 g (38% of theory)

Mp: 199.5 to 200 ⁰ C (Papers from acetone-ether)

C ₄₅ H ₆₈ O ₁₆ (865.034)

Ber. C 62.49 H 7.92

Gef. C 62.50 H 8,19

mass spectrum

m / 2 461 = Mt - 2acetylated digitoxose residues; m / z 306 = C ₁₉ H ₃₀ O ₃ (aglycone)

3 / S- (3 ', 3 ", 3'", 4 '''- tetra-0-acetyl-tri-D-digitoxosyloxy) -5j8,14 / S-androstane-14,17a-diol (V) A solution of 700 mg IV (8.1 χ 10 ~ ⁴ mol) in 17 ml 83% aqueous ethanol under stirring at room temperature with 36,7mg sodium borohydride (9.7 χ 10 ^"4 moie) was reduced after 30 minutes, with further 36.7 mg of sodium borohydride and stirred for a further 30 minutes at room temperature. The work-up begins with the acidification of the reaction mixture with 10% acetic acid. After extraction with chloroform, the extract is washed neutral with 10% potassium bicarbonate solution and water, dried with sodium sulfate and concentrated by evaporation in vacuo. evaporated. Column chromatography on 70 g silica gel 60 (0.063-0.200 mm, Merck, filling height: 16 cm) with chloroform-ethanol 98.5: 1.5. 98: 2 and 97.5: 2.5 as eluent gives 378 mg (54% of theory) of chromatographically pure 3 / 3- (3 ', 3 ", 3"', 4 "'- tetra-O-acetyl) tri-Drd-jitoxosyloxy) -5 / 3,14 / 3-androstane-14,17a-diol (V).

mass spectrum

m / z 290 = C ₁₉ H ₃₀ O ₂ (aglycone - H ₂ O); m / z 275 = 290 - CH ₃ ; m / z 272 = 290 - H ₂ O; m / z 257 = 275 - H ₂ O or 272 - CH ₃

3: 3 (3 ', 3 ", 3"', 4 "'- tetra-O-acetyl-tri-D-digitoxosyloxy) -5: 3,14i] -androstane-14,17a-diol-17-tosylate ( Vl) 170 mg of V (1.96 χ 10 " ⁴ moles) are dissolved in 6 ml of anhydrous pyridine and at 0 ° C with 74.7 mg of p-Toluensufochlorid (3.9 χ 10""moles) was added. After standing for 5 hours at about 3 ° C further 74.7mg p-toluene sulfochloride are added at 0 ° C. After standing for 5 days at about 3 ° C, the reaction mixture is left to remove the pyridine at about 6 ° C in a vacuum desiccator over concentrated sulfuric acid and potassium hydroxide. The chloroform extrate of the residue is washed with 3.5% hydrochloric acid, 10% potassium bicarbonate solution and water, dried with sodium sulfate and i. Vak. evaporated. The chromatographically pure 3β- (3 ', 3 ", 3'", 4 '''tetra-O-acetyl-tri-D-digitoxosyloxy) -5 / 3, i4 / 3-androstane-i4,17adiol-17-tosylate (IV) was obtained in a yield of 169 mg (84% of theory).

R _f 0.70 (DC precast plates Kieselgel 60 F 254, Merck; chloroform-methanol 36: 4)

3y3- (3 ', 3 ", 3'", 4 '"- tetra-O-acetyltri-D-di-9-nitoxosyloxy) -170-azido-5 / 8,14β-androstane-14-ol (VII) A solution of 150 Vl mg (1.47 x 10 ^J moles) in 1.5 ml of anhydrous dimethylformamide is treated with 73.6 mg of dry sodium azide (1.13 x 10 ^-3 moles) were added and maintained at 150-160 ⁰ C for 2 hours. then, Ice water, extracted with chloroform, the chloroform extract washed with water, dried with sodium sulfate and concentrated by evaporation in vacuo, purified by column chromatography on 20 g of silica gel H (type 60, Merck, filling height 7.4 cm) with di-n-propyl ether-ethanol 99 , 5: 0.5 as eluent provides 27 mg (45% of theory - based on reacted starting compound) chromatographically pure 3 / 3- (3 ', 3 ", 3'", 4 '"- tetra-O-acetyl -tri-D-digitoxosyloxy) -17 / 3-azido-50,14y8-androstane-14-ol (VII).

mass spectrum

m / z 460 = MT - 2 acetylated digitoxose residues; m / z 304 = Ci ₉ H ₃₀ NO ₂ (aglycone - N ₂ - H j

ß, 14/3-androstan-14-ol (I, R ¹ - R ³ = H, R ⁴ = "CH *. R ⁶ = tri-D-digitoxosylrest

To a solution of 23,5mg lithium aluminum hydride (6.2 χ 10 ^"(6 MOIE in 2 ml of anhydrous tetrahydrofuran in a stream of argon at room temperature for ⁴ moie) Jn2,5ml anhydrous tetrahydrofuran, a solution of 3 26,8mg VII χ 10) is" slow

dropwise. 40 minutes after the beginning of the addition, the reaction is stopped at ⁰ ° C. with 0.5 ml of methanol. The mixture is treated at 0 ° C with 3.5 ml of 10% sodium potassium tartrate solution, extracted with chloroform, the chloroform extract washed neutral with water, dried with sodium sulfate and i.Vak. evaporated. After purification by column chromatography on 2 g of silica gel 60 (0.063-0.200 mm, Merck; filling height: 5.5 cm) with chloroform-methanol 90: 10.85: 15 and 80:20 as eluent, 16.5 mg (79% of theory) are obtained .) Chromatographically pure 3/3-tri-D-digitoxosyloxy-17j3-amino-5 (3, ^ / S-androstane-K-ol (I, R ¹ - R ³ = H, R ⁴ = CH ₃ , R ⁵ = Tri-D-digitoxosylrest), mp: 215-218 ⁰ C (dec .; colorless crystals)

IR spectrum

1665cm " ¹ (primary NH ₂ group) mass spectrum

m / z 306 = C ₁₉ H ₃₂ NO ₂ (aglycone H); m / z 290 = aglycone - NH ₃ or aglycone - OH; m / z 273 = 290 - NH ₃

Claims (1)

Invention claim: Process for the preparation of 17/3 amino-5/3, l4 / 3-androstane-14-ols of general formula I. R ⁵ O 2 I, wherein R 'is a hydrogen atom or a hydroxy group, R ^{2 is} a hydrogen atom or a hydroxy group, R ^{3 is} a hydrogen atom or a hydroxy group, R ^{4 is} a methyl, hydroxy methyl or aldehyde group and R ^{s is} a hydrogen atom or a monosaccharide or oligosaccharide residue in glycosidic bond mean, characterized in that a corresponding card-20 (22) -enolol or a corresponding card-20 (22) -enolidglykosid of the formula II