DD235649A1 - PROCESS FOR PREPARING 17BETA-AMINO-5BETA, 14BETA-ANDROSTAN-14-OLENE - Google Patents

Abstract

According to the invention, a corresponding Card-20 (22) -enolide or Card-20 (22) -enolide glycoside is oxidized with selenium dioxide in boiling dioxane to the 17a-hydroxy compound, then the lactone ring is oxidatively decomposed at room temperature with potassium permanganate in acetone, the resulting 17-ketone with sodium borohydride in aqueous ethanol at room temperature to the 17a-hydroxy compound, this as 17a-tosylate with sodium azide in dimethylformamide at 150-160C to 17b-azide and the 17b-azide with lithium aluminum hydride in anhydrous tetrahydrofuran in an inert atmosphere at room temperature reduced to the target compounds and simultaneously deacylated. The compounds are purified by methods known per se. Field of application is the pharmaceutical industry.

Description

OH

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 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 is reduced to the 17α-hydroxy compound at room temperature, this is reacted as 17a-tosylate with sodium azide in dimethylformamide at 150-160 ° C to 17/3 azide, the 170-azide with lithium aluminum hydride in anhydrous tetrahydrofuran in an inert gas atmosphere, for example in a nitrogen atmosphere. or argon atmosphere, reduced at room temperature to the target compounds I and simultaneously desacylie Rt and the resulting intermediates and target compounds, if necessary, by 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-Amin0-5 / 3,14 / 3-androstan-14-ols of general formula I.

i ,;

-2- 743 38

wherein R ^{1 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, hydroxymethyl or aldehyde group and R ^{6 is} a hydrogen atom or a monosaccharide 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, Tetr., 23, 715-720, 1967). Nα-amino-anda-androstane derivatives have been reported by M. Davis, et al. (M. Davis, E.W. Parnell, D. Warburton, J. Chem. Soc. (C) 1698-1700, 1966) prepared from S, 3-acetoxy-n-tosyloxy-anda-androstane via the 17a-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 / 3,14 / 3-androstan-14-ols 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, 17/3 amino-5 / 3,14 / 3-androstane-14-ols 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 (22) -enolenglycoside 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 17a-hydroxy compound, then the lactone ring oxidatively degraded at room temperature with potassium permanganate in acetone, the resulting 17-ketone with sodium in aqueous ethanol at room temperature to 17a-hydroxy compound, this as 17a-tosylate with sodium azide in dimethylformamide at 150-160 ° C to 17/3-azide and 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 to the target compounds I at room temperature and at the same time desa cyliert. 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 17j8-amino-5 ^, 14ß-androstane-14-ols by the process according to the invention is surprising since the formation of 17/3 substituted 5/3, 14/3 steroids is thermodynamically far less favored than that of the corresponding 17a-substituted ones 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) causes the S / S-Tri-D- digitoxosyloxy-n / S-amino-S, 14/3-androstan-14-ol (I, R'-R ³ = H, R ⁴ = CH ₃ , R ⁵ = tri-D-digitoxosyl) inhibition of Na, K-dependent adenosine triphosphate phosphohydrolase of the human brain, which produces a positive inotropic effect on the insufficient 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-5 / 3.14 / 3-card-20 ( 22) -enolide {III) A solution of 5.5 g of 3 / 3- (3 ', 3 ", 3"",4"' - tetra-0-acetyl-tri-D-digitoxosyloxy) -14-hydroxy- 5, 8,14 / 3-card-20 (22) -enolide (digitoxin-3 ', 3 ", 3"', 4 '"- tetraacetate, II, R ¹ -R ³ = H, R ⁴ CH ₃ , R ⁵ = tetra-O-acetyl-tri-D-digitoxosylrest; 5,9x10 ^"3 moie) in 670 ml of dioxane with 3,44g of freshly sublimed selenium dioxide (3.1 x 10 ^-2 moles) were heated under reflux for 10 hours. The reaction mixture is after

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 | S ( 3 ', 3 ", 3'", 4 '"- tetra-O-acetyl-tri-D-digitoxoxyloxy) -14,17a-dihydroxy-5β, 14/3-card-20 (22) -enolide (17a) Hydroxydigitoxin 3 ', 3 ", 3'", 4 '' - tetraacetate) (III).

[a] _D + 46 ° (c = 2.23; EtOH)

UV: X _max 216 nm (e = 13100) '

3j8- (3 ', 3 ", 3'", 4 '''- tetra-O-acetyl-tri-D-digitoxosyloxy) -14-hydroxY-5/3-androstan-17-one (IV) 4g III (4 2.times.10.sup.- ³ moles) are dissolved in 175 ml of acetone and 6.55 g of potassium permanganate (4.2.times.10.sup.-2 mol) are added in portions at room temperature.After 1 hour from the beginning of the addition, the reaction mixture is worked up 1 g of sodium hydrogen sulfite in vacuo, and the solid residue was extracted several times with hot chloroform and then with chloroform from room temperature, the chloroform extract was washed with water, dried with sodium sulphate and concentrated by evaporation in vacuo.The 3j8- (3 ', 3 ", 3'"'4''- tetra-O-acetyl-tri-D-digitoxosyloxy) -14-hydroxyn-5 / 3,14β-androstan-17-one (IV) remains as a colorless solidified foam.

Yield: 1.4 g (38% of theory)

Mp: 19975-200 ⁰ C (acetone-Ehter leaflets)

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 / z461 = M ⁺ .-2-acetylated digitoxose residues; m / z 306 = Ci ₉ H ₃₀ O ₃ (aglycone)

3/3 {3 ', 3 ", 3'", 4 '''- tetra-O-acetyl-tri-D-digitoxosyloxy) -5j3,' Mß-androstane 'H, 17a-diol (V) A solution of 700 mg IV (8.1 χ 10 ~ ⁴ mol) in 17 ml 83% aqueous ethanol is reduced with stirring at room temperature with 36.7 mg of sodium borohydride (9.7 x 10 "" ⁴ moie). is After 30 minutes, After further extraction with chloroform, the extract is washed neutral with 10% strength potassium bicarbonate solution and water, and dried with sodium sulphate and i.vac .. Column chromatography on 70 g of silica gel 60 (0.063-0.200 mm, Merck; fill height: 16 cm) with chloroform-ethanol 98.5: 1.5, 98: 2 and 97.5: 2.5 as eluent provides 378 mg (54% of theory) of chromatographically pure 3 / 3- (3 ', 3 ", 3"', 4 "'- tetra-O-acetyl-tri-D-digitoxosyloxy) -5 / 3,14 / 3-androstane-14,17a-diol (V). ,

mass spectrum

m / Z290 = C ₁₉ H ₃₀ O ₂ (AgIYkOn-H ₂ O); m / z 275 = 290 -CH ₃ ; m / z 272 = 290 -h ₂ O; m / z257 = 275 -H ₂ O or 272 -CH ₃

3 (3- (3 ', 3 ", 3'", 4 '''- tetra-O-acetyl-tri-D-digitoxosyloxy) -5 -androstane-14,17a-diol-17-tosylate (VI) 170mg V (1.96 χ ^ O ^"4 moles) are dissolved in 6 ml of anhydrous pyridine and at 0 ⁰ C and 74.7 mg of p-Toluensufochlorid added (3.9 x 10 ^-4 moles). After 5 hours, left to stand at about 3 ° C are further 74.7 mg of p-Toluensulfochlorid at 0 ° C. After 5tägigem standing at about 3 ° C, the reaction mixture is allowed to stand over concentrated sulfuric acid and potassium hydroxide to remove the pyridine at about 6 ⁰ C in a vacuum desiccator. the Chloroformextrat of The residue is washed with 3.5% hydrochloric acid, 10% strength potassium hydrogen carbonate solution and water, dried with sodium sulfate and concentrated by evaporation in a vacuum. The chromatographically pure 3β- (3 ', 3 ", 3"', 4 "'- tetra- O-acetyl-tri-D-digitoxosyloxy) -5 / 3,14 / 3-androstane-14,17-diol-17-tosylate (IV) was obtained in a yield of 169 mg (84% of theory).

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

3 / 3- {3 ', 3 ", 3''' _/ 4 '' - tetra-O-acetyl-tri-D-digitoxosyloxy) -17 / 3-azido-5i3,14β-androstan-14-ol (VII) a solution of 150 mg Vl (1.47 x 10 ^"4 moie) of anhydrous in 1.5 ml of dimethylformamide (~ ³ moles of 1.13 x 10) was added mit73,6 mg of dry sodium azide and 2 hours at 150-160 ° C held. Then ice-water is added, extracted with chloroform, the chloroform extract washed with water, dried with sodium sulfate and concentrated by evaporation in vacuo. evaporated. Column chromatographic purification on 20 g of silica gel H (type 60, Merck; filling height: 7.4 cm) with di-n-propyl ether-ethanoI 99.5: 0.5 as eluent gives 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-5 / 3,140-androstane-14-ol (VII).

mass spectrum

m / z460 = M. ⁺ - 2 acetylated digitoxose residues;

m / z 304 = Ci ₉ H ₃₀ NO ₂ (aglycone - N ₂ - H) -

Sweet tri-D-digitoxosyloxy-n-amino-Bβ, 14/3 androstan-14-ol (I, R ¹ -R ³ = H, R ⁴ = CH ₃ , R ⁵ = tri-D-digitoxosyl

To a solution of 23.5 mg of lithium aluminum hydride (6.2 x 10 " ⁴ moles) in 2.5 ml of anhydrous tetrahydrofuran is added

'-' -T_4 .. "uwHrr.fnran in irnnnstmm at room temperature slowly

-Ί · - / «+ Ο OO

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 concentrated i. 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 eluant, 16.5 mg (79% of theory) are obtained. ) Chromatographically pure Sb tri-D-digitoxosyloxy-n-amino-S, 14/3 -androstane-14-ol (I, R ¹ - R ³ = H, R ⁴ = CH ₃ , R = tri-D-digitoxosyl ) from Mp: 215-218 ⁰ C (Zers., colorless crystals)

IR spectrum

1665C1TT ¹ (primary NH ₂ group)

mass spectrum

m / Z306 = C ₉ H ₃₂ NO ₂ (aglycone - H); m / z 290 = aglycone - NH ₃ or aglycone - OH; m / z 273 = 290 -NH ₃

Claims (1)

-1- 743 Invention claim: Process for the preparation of 17/3 amino-5 / 3,14 / 3-androstane-14-ols of general formula I. 2 I, wherein R ^{1 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, hydroxymethyl or aldehyde group and R ^{5 is} a hydrogen atom or a monosaccharide or oligosaccharide residue in glycosidic bond , characterized in that a corresponding card-20 (22) -enolide or a corresponding card-20 (22) -enolidglykosid of the formula II