DE1957246A1 - Process for the preparation of 3beta-hydroxy-5beta-cardenolides - Google Patents

Description

FARBV / ERKE HOECHST AG., Formerly Master Lucius & Brüning File number: Pw 6256

Date: Nov. 13, 1969

"Procedure ζ ur .. He r st e 1.1 u η g of .3 ^ --- Hy dr oxy - 5.ß -ca rcle nc 1 ide 11"

From the Belgian patent no. 707-326 is already known to produce; 5ß-hydroxy-5ß-cardenolide, where] 5-keto-5ßcarderiolide is first reduced with complex metal hydrides to the corresponding 3 ^ -hydroxy compounds and these are then converted into 3ß-cardenolides ^{by Waiden 1 see reversal} v / earth.

It has already been suggested that 3β ~ hydroxy ~ 5β-cardenolide by producing] 5-keto-5ß-cardenolide with Aluminum alcoholate reduced by Meerwein-Ponndorf and the separates 3 ° \ -hydroxy-cardenolides formed at the same time in approximately the same amount, converting them to 3-keto-5β-cardenolides dehydrated again, after which she again did the Meerwein-Ponndorf reduction can be subjected.

The present invention relates to a simple and smooth process for the preparation of 3ß-hydroxy-5ß-cardenolides the 14-dehydro- or I4ß-series that thereby is characterized in that one corresponding 3-keto ~ 5 ~ cardenolide with iridium (IV) hydrochloric acid, the alkali or Ammonium salts or iridium (III) chloride in the presence of Trialkyl phosphite and lower alcohols.

In the case of apiels, the procedure is as follows Form lnoherna:

10982 1/2 199

BAP OBiGiNAL

Fv; 6256

Ir ^J

Corn as raw materials. for example in question:

or
-eriolid ?. 0 (22) - ir - Koto-l ⁱ eat "hydroz / -5ß-card;

10 9 8 2 1/2199

BATH ORIGINAL

• Fw 625Ö-

The reduction is in conventional V ^<r else .durchgeführt by the soluble iridium (IIl) - BZV /. (IV) -sals, of which catalytic amounts are preferably used, in low molecular weight alcohols in the presence of trialkyl phosphite for a long time, about 1 to 5 days, preferably 50 to 1-50 hours, heated to boiling under reflux. The lower alcohols used are advantageously 2-propanol, which advantageously contains up to 10 % water. The trialkyl phosphite used is advantageously trimethyl phosphite, at least in stoichiometric amounts. You can work with or without the addition of a little mineral acid. When using Iridturn (III) chloride in the 14-dehydro series, the addition of a little concentrated hydrochloric acid is advantageous.

The j5-keto-5ß-cardenolide to be reduced can either immediately or first after a few hours (up to 15 hours) to the reduction mixture are given. After the end of the reaction, the reaction mixture is removed from the aqueous solution, e.g. by suction or Extracting with organic solvents, removed.

The advantage of the method according to the invention over that from Belgian patent no. 707 326 known method is based once in the. Saving of several reaction stages. In the known process, it is first reduced, then esterified with p-toluenesulphochloride and this finally rearranged with potassium formate (Walden inversion). The total yield is about 40 %. In contrast, in the process according to the invention, the reaction with p-toluenesulphonyl chloride and subsequent Waiden's-see reversal is not necessary, and yields of over 90 % are obtained.

The reduction of J-keto-androstane and 3-Ke to-pregnane derivatives to the corresponding axial jJ3 -Hy ar oxy connections irjt in J.Chew.Soc. (C) (19 ^ 9) "Pages Io5." 5-1659.

⁺ ) with iridium (IV) hydrochloric acid

/ 4 109821/2199

Fw 6256

The use of the same reducing agent on steroids containing the sensitive cK, ß-unsaturated lactone ring must appear doubtful in view of the last-mentioned reference. In the known reaction, only the reduction of saturated keto steroids had been described, it had to be done with an - un-

ί desired - action of the reagent on double bonds,

e.g. in the 14,15 position of steroids. For example, there would have been a partial conversion of the thermodynamically labile cardenolides of the 1'4-dehydro- or I4ß-series into the fe more stable 8 (14) or 8 (9) -Dehydrocardenolide or -Isocardenolide can take place. In addition, it is known from the cited literature that, for example, Pregnan-20β-oil or 21-hydroxy-pregnan-20-one can be attacked by the reagent in a way that cannot be overlooked. The Pregnan-20-on-side chain in turn suffers epimerization in IT position.

By means of the method according to the invention it is now surprising R occasionally possible, in a smooth reaction with very good yields to the important 3β series of. Digi-toxigenin steroids to get; you get either in the 14ß-hydroxy. series directly the highly effective cardiac remedy digitoxigenin or 'arrives at its precursor, 14.20 (22) -dienolide, polygamy be converted into digitoxigenin by known methods can.

/ 5 109821/2199

B ¹ W 6256 '- 5 -

example 1

3β- hydroxy-5β-carda-14,2o (2 2) -di enolide

20 ecm of trimethyl phosphite and 500 mg of iridium (IV) hydrochloric acid are added to a stirred suspension of 10 g of 3-keto-5ß-carda-14, 20 (22) dienolide in 250 ecm of 90 tiger propanol-2. The reaction mixture is then heated to boiling for 62 hours with stirring and under reflux cooling. After 49 hours, all the starting material has gone into solution. After the total reaction time has elapsed, the clear, almost colorless solution is stirred into 1 liter of water. The precipitated reaction product is filtered off with suction, washed with water and taken up in methylene chloride. After washing with water and drying over sodium sulfate, it is concentrated to dryness in vacuo. After recrystallization from methylene chloride / methanol 9.15 g of 3.beta.-hydroxy-5ß-carda-14,20 (22) -dienolid a melting point of I95 to I99 ⁰ C (corr.)

[cX] _D = -28 ° J [<*] j ₆₅ = -160 ° (chloroform 0.5 %) .

Can erhalten'werden ^ -hydroxy-5ß-carda-l4,20 (22) -dienolid a melting point of I96 ⁰ C by means of chromatography about 4θΟ mg (== 4%) 5 from the mother liquors.

, 14ß-Dihydroxy-5ß-card-20 ( 2 ?.) -enolide (Dlgltoxisenin)

To a solution of 5.0 g of j5-keto-l4n-lvdr-oxy-5G-card-20 (22) '- cnolLd in 250 ml propanol-2 (90%) 10 ml trircethyl-

/ 6 109821/2199

Fw 6256 - 6 -

phosphite and 250 mg of iridium (IV) hydrochloric acid. The reaction mixture is then refluxed for 140 hours. It is then cooled rapidly and stirred into 4θΌ ml v / water. It is then extracted with chloroform. The extract is washed neutral with water / water, dried over sodium sulfate and concentrated to dryness in vacuo. After recrystallization from acetone / petroleum ether 4.25 S digitoxigenin of melting point 240-242 ⁰ C obtained [o (] _B = 18.1 ° C (in CHCl _5).

109821/2199

Claims (1)

Fw 6256 - 7 - Patentanspru ch Process for the preparation of 5 [beta] -hydroxy-5 [beta] -cardenolides
the 3A-Dehydro- or I4ß-series, characterized by
that one corresponding j5-Ke.to-5ß-cardenolide with iridium (IV) · hydrochloric acid, its alkali or ammonium salts
or treated iridium (III) chloride in the presence of trialkyl phosphite and lower alcohols. 109821/2199