DE1961034B - Process for the production of pure digoxin monomethyl ethers - Google Patents

Description

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It is known that digoxin derivatives. in which one or two hydroxyl groups of the digiioxose residues are etherified by alkyl residues with 1 to 2 carbon atoms, are absorbed enterally better than digoxin itself and are therefore very well suited as orally administered therapeutics for the treatment of cardiac insufficiency in humans (cf. Dutch interpretative publication fiS 134O ¹ ) ).

Animal experiments and extensive clinical observations have now shown that two monomethyl ethers of diaoxin of particularly great value for the treatment of the weak heart muscles are: This is the 3 "'- O-methyldigo \ in and especially the 4 "" - O-Meihy! Digoxin.

Both connections can be made according to the method of the Dutch patent specification fiS 13409 by reaction with customary O-Methviierungsmittcln. such as dimethyl sulfate or diazomethane, under the process conditions known per se produce. J, but it was the one mentioned above on the priority day Registration neither the e \ a! ;; e constitution the Dicoxinmonome'hvlLither known nor was it possible the methylation reaction without application (.Ls toxic and explosive diazomethane *, which is hardly suitable for a large-scale production process comes into question, at the monomination stage to stop.

Experienced in the usual methylation, e.g. : ■ !!! Dirre'lnKuKai. escape i: i considerable amounts (20 to 30 ", -,) digovin polyethers, which can no longer be digested or monomethyl digoxin entirety. This means a considerable loss of expensive storage material . which cannot be increased by the fact that. ' the ¹ Jev, ünscht ·.
Mcnomethyl-iither must be separated from the Polymethyl-äib.c: i c'nr'Miii'iograpiii ^ cii. Such k; i!: - e- when working up the reaction mixture according to the 'method of the Dutch Au ^' eje ^ ehrift TiS 13 - '. OO it can happen that Dicitoxo ^ e is abücspalfen, whereby un'-ira'. ich'v.re ·. Dv; <> xir.enin disfigured.

We have now found that one can avoid the use of the two digoxin mnnomethyl ethers mentioned above by the intrinsic control of Diüovin with Dimctlr.lsulf ::! in nimetln'formamide in ^l "ie :: enwarl of Bariumrn J r <■>χ;. d surprisingly pure; v.vi; v nen · .mn. that the R'akli.uisgemiseh either Aliüniiiiimi.ixyd and an inert organic I.ö ^ miv: mi '!. ·! or Muminiumi ^ oprop '.' lat zuel / i. the \ n \ - L'e! eini ".ie and tnii chloroform \ erdün:; 'e reaction mixture with I'xrulin ·. ei-ei / i. im \'; \: uum ein-: t and in Mi see (lekann'er V -. 'ei'-e \ on iue! i' umnevi / -lem digoxin separates.

The main advantages of the invention \ 'crfahri; ns consist in the fact that the application of Diazomethane can be completely avoided that Polvm tliyldigoxine to such a minor extent arise that on a clm-miiatographic cleaning can be dispensed with and that the methylamines depending on Wuiv-ch exclusively on the 3 '"- or'!" '- hydroxyl group of the digitoxose residue can be selenkl.

The inventive method cheaper! the Production of these valuable cardiac glycosides also significantly, because the recycling of the separated Digoxins in the methylation process an almost complete conversion of the valuable starting product Diüoxin enables.

The elucidation of the structure of the erfindül.l obtained monomethyl ether of digoxin by partial hydrolysis with 0.05 η hydrochloric acid to digoxi-.jenin-mono-digkoxosid. Digoxigenin-bis-digitoxo-id and disoxiaenin as well as through complete acid cleavage H.ln Schwe: 'acid and evidence of the split off cymarose d 4-0-methyldigitoxose

ι eräab. that through the addition of aluminum oxide and an inert organic solvent 4 "'- O-meth \ ldigoxin is formed while the reaction with the addition of aluminum isopropylate leads to the 3 "'- O-MethyV: goxin.

All solvents miscible with dimethylformamide come as inert solvents in Fra: ■. which of dimethyl sulfate under the reaction conditions not be attacked; the Me: i__e of the added solvent must be from Fa !! :;

in case to be determined. The addition corresponding to the Me: i_v dimethylformamide used has s.j'-. proved to be aünstia. <L--> has proven particularly useful for this purpose. In addition, v: ·.-Benzene. Dioxane. chlorinated K-ililenwasserstotTc v ..

Ethylene chloride or chloroform and Cvclohe-. ·. ■ use.

The work-up and purification of the received. Mixture * au? Disoxin monomethyl ether and n: .. ' reacted digoxin success; nae / · der Li: .'tu :. '

of the "crude product in a vacuum unier P ;. ridinzu -;. · according to the principle of multiplicative distribution: ·· for example with chloroform-Tctrachlorkohlensv ■ <■ '- methanol-water (1: 1: 1: 1 ;. where the respective''
() -Meth \ lather of digoxin after concentration

3 :. organic phase and recrystallization. ivispie 'wise from acetone, pure. Pas in the v. iu'ri
Pha-e located Dig -.- xin becomes with Γ! Ι! Μ: ^ ::>
extract 'and a further Nfethslierimg -.'. org .. :: ■ ziiL-led.

4 "" in the following terms; - ^; e! en vi "d da-- ertin · ¹ -; ^1. <: em: i! '·' - · \ 'find out more crlaute ;;.

!! e i s ρ i e '!

1 ::!): ·. '■■ ixin and 300 mi; Aluminum -'- opnv ;. ^! 'become·.' in ■ · ml of dimethylformamide: vlö '; and <\; e '· Zuuabc of 5SIl η ve: Bariu'vhuiroxvd inner R \:' ,: - at room'empcrati'r mil 0.S ml ni'iieUr.K'.ilh't ·. since. Then 4 hours of Ivi Rairv.-cnviera ', ··; touched. mi; 50; · ι! Chloroform compounds. "ibe ^r Κί ·>;! - •; ur; '. b.:.: · .ι.ΐι: ί. with chloroform n; ::! u'ev.'. shy, m-4ml rvridin versei / t and in \ '. a'aium ei-vee "; · f) the residue was shaken out in chloroform a'. 'f (.' e! '" m ", ie'i and three times with water. The jiesan: melt washing water are extracted once more with chloroform and the combined chloroform phases, after drying over sodium sulphate, concentrated in vacuo : 1: 1). After concentration and crystallization from acetone, the organic phase yields 510 mg of 3 "'- O-Mcth \ 1digo \ in: Mp. 226 to 229" C.

The digoxin in the aqueous phase is extracted with chloroform and another Mcthvlierunt'ssane / uweführung.

Claims (1)

Example 2 ] 00g Digüxin are dissolved in SOOmI dimethylforma with gentle warming. Then 50 ml of toluene are diluted with 50 ml, 60 g of barium hydroxide and 50 g of aluminum oxide (according to Brockmann) are added and 50 ml of dimethyl sulfate in 800 ml of toluene are added dropwise with stirring at room temperature over 60 minutes. The mixture is then stirred for 20 to 24 hours at room temperature, diluted with 2.4 l of chloroform, suction filtered over 100 g of kieselguhr, washed with 2.41 of chloroform, treated with 400 ml of pvridine and concentrated in vacuo to a viscous residue. This is taken up in 3 l of chloroform and extracted three times with 500 ml of water. The collected washing water is extracted once more with 500 ml of chloroform and the combined chloroform phases are dried over sodium sulfate and concentrated in vacuo. The residue is then subjected to a multiplicative distribution with the phase mixture chloroform / carbon tetrachloride / methanol / water 1: 1: 1: 1 in order to separate methyl digoxin and digoxin. After concentration and crystallization from acetone, the organic phase yields 46 g of 4 '"- Q-methyldigoxine; melting point 226 to 229 ^: C. The digoxin in the aqueous phase is extracted with chloroform and another Methyl ierungsgang supplied. _1Q claim: VenYhren riiir Heritelhin .: \ on pure digoxin monomethyl ethers by reacting digoxin with dimethyl sulfate in dimethylformamide in the presence of barium hydroxide, thereby characterized in that either aluminum oxide and adding an inert organic solvent or aluminum isopropoxide which The reaction mixture diluted with chloroform is concentrated in vacuo with the addition of pyridine and then separating it from unreacted digoxin in a manner known per se.