DE1084718B - Process for the manufacture of secosteroids - Google Patents

Description

It has already been proposed to use 5,6-seco-5,6-peroxydo-3-hydroxy- or -S-acyloxy-S-hydroxy-ö-alkoxycholestane to be catalytically hydrogenated in stages, with 3 / J-hydroxy- or -acyloxy-S.o-secocholestan-S-on-o-ale are obtained as products of the first hydrogenation stage. It has also been suggested to include these aldehydes in their Transferring phenylhydrazones (German patent application F 26109 IVb / 12o).

It has now been found that these 3 /? - hydroxy resp. -acyloxy-S.o-secocholestan-S-on-ö-alphenylhydrazone reduced can become 3 / S-hydroxy- or -acyloxy-S.ö-seco-S-hydroxy-o-aminocholestanes. In addition to the phenylhydrazones mentioned, the corresponding derivatives of others in the 5 (6) position can also be unsaturated Sterols, e.g. B. sitosterol, the reduction carried out according to the invention are subjected.

If this reduction is carried out catalytically over platinum in ethyl acetate up to the uptake of 6 mol of hydrogen, the Sjö-Seco-S / JS-dihydroxy-ö-aminocholestane or its 3 / J-acyl derivatives, in which the 3 /? - hydroxyl group can be exposed by saponification, whereby S.ö-Seco-SjS.S-dihydroxy-ö-aminocholestane is also obtained. 3 mol of H ₂ are consumed in this reaction to hydrogenate the phenyl radical. The same compound is also obtained if the phenylhydrazones used as starting materials are first reduced with lithium aluminum hydride to S.ö-Seco-S ^ .S-dihydroxycholestane-o-alphenyl-

CH

LiAlH,

RO '

Method of manufacture
of secosteroids

Applicant:

Paint factories Bayer Aktiengesellschaft, Leverkusen-Bayerwerk

Dr. Hans Lettre and Dipl.-Chem. Rolf Pfirrmann,

Heidelberg,
have been named as inventors

hydrazone and this subject to catalytic hydrogenation.

However, one can also proceed in such a way that the phenylhydrazones serving as starting materials are initially used catalytically to Sß-hydroxy- or -acyloxy-S.ö-seco-S-hydroxycholestane-6-alphenylhydrazones hydrogenated, this further hydrogenation to 3 / J-hydroxy- or -acyloxy-S ^ -seco-S-hydroxy-ö-aminocholestanes subjects and in these if necessary exposes the 3-position hydroxyl group. The course of the reactions can thus be illustrated by the following partial formula scheme:

CH,

CH,

catalytic

CH ₂

HN-N = CH

C ₆ H ₅

RO

HN-N = CH

C ₆ H ₅

catalytic

lyrical

HO

RO

catalytic

NH,

NH,

In these formulas, R denotes hydrogen or a 50. The products of the present process are intended as Acyl group. The medicinal products or as intermediates for the manufactured according to the present process Amines can be substituted on the nitrogen atom and quaternary according to methods known per se

Ammonium compounds are transferred.

in the preparation of medicinal products. Their most valuable property is their cytotoxic effect normal and malignant cells.

009 549/426

Claims (1)

3 4 Example 1 100 ecm of ethyl acetate up to the absorption of 1 mol of H ₂ 1 g SjS-Acetoxy-S.o-secocholestan-S-on-ö-alphenylhy- hydrogenated. The residue of the filtered solution becomes out drazon is recrystallized in 150 ecm glacial acetic acid over platinum (methanol-ethyl acetate produced. 800 mg are obtained from 50 mg PtO ₂ ) bis. for up to 6 moles of H ₂ Sß-acetoxy-Sjö-seco-S-hydroxycholestan-o-alphenylhy- hydrogenated. The filtered solution is concentrated in vacuo. 5 drazon, yellow needles with a melting point of 194 ° C .; Max. evaporated and the residue was stirred with water. 270 πιμ. in alcohol. The amorphous powder is centrifuged off and CHNO 2 crystallizes it from methanol, using 350 mg long needles of ³ IL ^{56 2} f S ^ acetoxy-S.O-seco-S-hydroxy-cholestane-o-ammonium- Calculated C 76.05, H 10.20, N 5.07; Acetate with a melting point of 198 ° C (decomposition) is obtained. io found C 76.27, H 9.85, N 5.18. The yield is 40% of theory. The product goes into the further hydrogenation C H NO S / S-acetoxy-S.ö-seco-S-hydroxy-ö-aminocholestan and ^{31 57 5} "in the saponification in S ^ -Seco-S / S-dihydroxycholestan- Calculated C 71.08, H 10.97, N 2.67; 6-alphenylhydrazone over. Found C 71.19, H 10.29, N 2.80. 15th The free amine could not be obtained in crystalline form; eispie However, it forms the following crystallized derivatives: N-Ben- 1 g Sß-acetoxy-S.o-seco-S-hydroxycholestane-ö-ammo zoyl derivative, m.p. 262 ° C, needles. Nium acetate is dissolved in 20 ecm of 85% formic acid Γ H NO and on the water bath for 2 hours with 2 ecm aqueous ^{36 S7} * 20 ger 40 ° / {^ 6Γ formaldehyde solution heated. One steams Calculated C 76.15, H 10.12, N 2.46; _{then in a} vacuum, dilute sodium hydroxide solution is added and Found C 76.24, H 9.85, N 2.40. _{athert from the residue of the} washed and dried Benzylidene derivative, m.p. 245 to 246 ° C, needles. neten ethereal solution is recrystallized from ethyl acetate _ .__ -_ _ siert. 65 is obtained in ° / ₀ yield 5,6-seco-3 / S, 5-dihydroxylation ^{36 δ7 3} "" 25 droxy-6-dimethylaminocholestane, colorless needles from Calculated C 78.36, H 10.41, N 2.54; Melting point 172 ° C. Found C 78.59, H 10.22, N 2.71. Hydrochloride F. 280 to 283 ° C, matted needles made of When the amine is saponified with methanolic potash-methanol-Essjgester, which turn brown from 250 ° C, caustic at room temperature does not produce the crystalline > ■ ·. 1 c sierte S.o-Seco-S ^ .S-dihydroxy-o-aminocholestane; it forms 3 ° ^{e S} ^ ^ie a crystallized benzylidene derivative, mp 231 ° C, needles. An essential solution of 0.2 g of 5,6-Seco-3jö, 5-dihy- _ " _N _ droxy-6-dimethylaminocholestan is 4 weeks at ^{34 55 2} room temperature with excess methyl iodide Calculated C 80.10, H 10.87, N 2.75; left behind. 0.2 g of 5,6-Seco-3 / S, 5-dihy- Found C 80.08, H 10.54, N 2.85. ₃₅ droxycholestan-o-trimethylammomum iodide and recrystallized it from ethyl acetate. Small needles are obtained Example 2 _, melting point 194 ° C. 0.2 g S / S-acetoxy-Sjo-secocholestan-S-on-o-alphenyl-CH TNO hydrazone are reduced in 50 ecm ether with LiAlH _4. ³⁰ ", ² ', _{rnnQ9 w Q RR ΛΤ} ο vi τ cm as ■ , Ζ τ. »Li j -u · λ λγ \ ccc ίο c jL. j χ. ι Computes GoU, y. £, Hy, ö <5, JN Δ.6Ι, J / 1.45, 140 mg So-Seco-Stf.S-dihydroxychole- 4 ° _f ■,, - ^ _n W trnm χτom τ ^ are obtained X ^ i-U 11-j it. -KT Ji o "ι found C 60.62, H 9.02, N 2.02, 120.74. stan-6-alphenylhydrazone; yellow needles from the enamel ° point 203 to 204 ° C (methanol). QsH ₅₄ N ₂ O ₂ PATENT CLAIM: Calculated C 77.58, H 10.65, N 5.48; ₄₅ Found C 77.33, H 10.43, N 5.45. Process for the production of secosteroids, since The maximum of the UV absorption in alcohol is characterized by the fact that 3 /? - hydroxy resp. 270 ηαμ. In the catalytic hydrogenation, the pro-acyloxy-S.o-secocholestan-S-on-ö-alphenylhydrazones goes duct over into amorphous S.o-Seco-S / J.S-dihydroxy-o-amino- or the corresponding derivatives of others in 5 (6) -stel- cholestan. 50 reduction of unsaturated sterols in a known manner B eis · el 3 adorns, in the reduction products, if necessary, the 3-position hydroxyl group is exposed and the thus obtained 1.3 g of S ^ -Acetoxy-Sjo-secocholestan-S-on-o-alphenyl- tenen amines optionally on the nitrogen atom in hydrazone is substituted or made quaternary over Pt (produced from 50 mg PtO ₂ ) in a known manner. r 009 549/426 6.60