DE2826532C3 - Process for the isolation of ß-acetyldigoxin from the crude product of the partial acetylation of digoxin - Google Patents

Description

The present invention relates to a method for isolating jJ-acctyldigoxin from the crude product of partial acetylation of digoxin.

0-Acelyldigoxin belongs / u to the most important biological active digoxin derivatives and is used because of its particularly favorable cardiotonic effect in used in the treatment of a number of heart diseases.

In the partial acetylation of digoxin with acetic acid:) hydride in pyridinic solution can be carried out by the correct choice of reaction conditions will make the monoacetyl esterification reaction so successful be carried out that a product is formed, which 75 to 80% 0-acetyldigoxin and 20 to 25% others Admixtures, d. H. Di- and polyacelyldigoxin. nt-acctyldigoxin and contains unreacted digoxin.

For cleaning and isolation of JSS acetydigoxin and related compounds from raw Acetylgcmischcn and similar reaction products /.B be in the Palentlitcratur. in PLPS 54 579, GB PS II 62 614. AT-PS 2 32 189 and in DEPS 16 68 239 two methods are cited, namely the distribution between two solvent phases and the column chromology aphic.

By applying the method of multiple distribution between the phases of a severe and We have not obtained satisfactory results in our experiments using a light solvent Various combinations of solvents, e.g. B. chlorinated hydrocarbons / nicdcralkanols / Water, chlorinated hydrocarbons / water / water, Ethylacclate / water, benzene / melhanol / water, toluene / Methanol / water, chlorinated hydrocarbons / toluo | / meihanol / water, checked. The separation of the main components d. H. from / J-acetyldigoxin and not converted digoxin, was not successful enough, so that the mixed product was still due to recrystallizations had to be cleaned, which, however, the yields were considerably reduced.

Neither were the attempts to purify the crude acelyl product by means of column chromatography achieves useful results. There were two

to commonly cited in the literature and otherwise the most suitable adsorbents, aluminum oxide (activity 1 to 2 according to Brockmann) and silica gel as stationary phases and a range of solvents tested as moving phases. Because of proportionately poor separation of the individual acetyldigoxine components and because of partial isomerization of ß-Acetyldigoxin to the α-form were the hallmarks of today pure product low.

A disadvantage of the above methods is also their lengthiness and the use of large amounts of Solvents and adsorbents, their recovery is quite problematic.

It has now been found that two successive recrystallizations of the crude product the partial acetylation of digoxin from two different mixtures of selective organic Solvent a good separation of the undesired impurities, which are practically completely in the Crystallization liquors remain dissolved, from the main

jo standieil, d. H. 0-acetyl digoxin. which one after each Recrystallization from the solutions in a purer one Form is eliminated. A previous purification of the crude product of the partial acetylation of digoxin using the distribution method or

J5 column chromatography is not required.

The seduction according to the invention is characterized by that as the first step the crude product at the reflux temperature in the first solution mill combination is dissolved and which after cooling on

■ Crystals precipitated at room temperature isolated which as the second step at reflux temperature be dissolved in the second solvent combination, and that after cooling to room temperature precipitated crystalline product is isolated.

Y) where, as the first and the second solvent combination, acelon / n-hexane and (. "

• so it has been found that favorable L / gcbnissc achieved if the solvent combinations in the following volume ratios are used: Accton / n hexane I: 4 I: 6. preferably 1.5. and chloroform / toluene 1: 4 1: 7. Preferably 1: 5. Or Mclha

v, nol / water 1.1: I 1.4. I. preferably 1.2: I. and methylene chloride / ether I: 6 1 .8. preferably 1: 7; however, the best results are obtained with the combination of methylene chloride / carbon dioxide 1: 4 1: 7, preferably 1: 5, and methanol / water 22 : 1 - 2.4, preferably 2.3: 1.

The selective recrystallization according to the invention jf-acetyldigoxin obtained in a 70 to 75% Auübcutc corresponds with respect to the Quality according to chemical standards and pharmacological regulations,

The inventive method for isolating 0-Acctyldigoxin from the crude product of the acetylation shows in comparison to the other, from the Palcnllitcra-

IQ

20th

for known methods the advantages of a simpler one Implementation on an industrial scale, a lower consumption of inexpensive and easily accessible commercial solvents and higher yields of / J-acetyldigoxin with unchanged Quality on.

The process is explained in more detail using the following examples

example 1

42 g of dried crude product from partial acetylation of digoxin are dissolved in 480 ml of acetone under reflux and the solution is stirred with 2400 ml of η-hexane are added. The fine crystals, which begin to separate out immediately, will reach room temperature Left to stand for 5 hours, filtered off with suction, washed with n-hexane and dried at 40 ° C. in vacuo.

Yield: 32 g of crude / J-acetyldigoxin (product I).

31 g of the product are dissolved under reflux in 500 ml of chloroform; 2500 ml of toluene are added while stirring. Crystals which precipitate from the solution after standing for an hour at room temperature are filtered off with suction, washed with toluene and ether and dried in vacuo. Bulge: 29 g of 0-acetyldigoxin (product II), / λ / "'= + 29.1 ° (c = 1, pyridine). Mp. 170 °, 249-25PC.

The filate obtained after the product I has been filtered off with suction is evaporated to dryness in vacuo. Of the Residue, which mainly contains non-converted digoxin, is obtained by recrystallization from pyridine / ether / jo Purified water (3.5: 5: 40) and used for another acetylation.

The obtained after suction dos Prod ^ Kles II Filtral is replanted to dryness. The residue contains di- and polyacctyl derivatives of i igoxins, which on known way to be eniacetylated to dogoxine, which is returned to the process.

Example 2
30 g of dried crude product of the partial Accly- w-regulation of digoxin dissolved in 900 ml of 55% aqueous methanol are dissolved under reflux, and allowed to stand for 5 hours at room temperature. The precipitated crystals are filtered off with suction, washed with cooled 55% strength aqueous methanol and then with ether and ^{dried at 40 °} C. in vacuo. Yield: 23 g of crude i-acetyl digoxin (product I).

22 g of product I are dissolved under reflux ic 330 ml of methylene chloride and the solution is mixed with 2300 ml of ether while stirring. The crystals, which begin to separate out immediately, are left to stand at room temperature for 4 hours, filtered off with suction, washed with ether and dried in vacuo. Yield: 17.7 g of 0-acetyldigoxin (product II). / Λ / ί "" = + 29.8 ^U (C = 1, pyridine), m.p. 170 ° .248-251 "C.

Both filtrates obtained after recrystallization are treated analogously to Example 1.

Example 3

84 g of dried crude product from the partial acetylation of digoxin are dissolved in 970 ml of methylene chloride dissolved under reflux and the solution is mixed with 5000 ml of carbon tetrachloride while stirring. The crystals which begin to separate immediately, are left to stand at room temperature for 5 hours, suctioned off, Washed with carbon tetrachloride and then with Ätlier and dried in vacuo at 40 ° C. Yield: 77 g of crude 0-acetyldigoxin (product I).

76 g of the product I are dissolved under reflux in 2280 ml of 70% strength aqueous methanol and the solution is left to stand for 5 hours at room temperature. The precipitated crystals are filtered off with suction, washed with cooled 70% aqueous methanol and then with ether and dried in vacuo. Yield: 61.5 g of ^ -acetyldigoxin (product II). / λ / ' ¹ "= + 29.4 ° (C = I, pyridine), m.p. 170 °, 249 -252 ° C.

Both filtrates obtained after recrystallization are treated analogously to Example 1.

Claims (2)

28 claims: 1. Method of Isolating / f-Acyldigoxin from the crude product of the partial acetylation of digoxin, characterized in that that the first step is the crude product at the reflux temperature in the first solvent combination is dissolved and the crystals separated out after cooling to room temperature isolated, which as a second step at reflux temperature in the second solvent combination are dissolved, and the precipitated crystalline after cooling to room temperature Product is isolated, with acetone / η-hexane and chloroform / toluene or methanol / water and methylene chloride / ether or methylene chloride / carbon tetrachloride and methanol / water can be used. 2. The method according to claim!, Characterized in that that acetone / n-hexane in a volume ratio of 1: 4-1: 6, preferably 1: 5, and chloroform / toluene in a volume ratio of 1: 4-1: 7, preferably 1: 5, can be used. Methanol / water in a volume ratio of 1.1: 1- 1.4: 1, preferably 1.2: 1, and methylene chloride / ether by volume 1: 6 - 1: 8, preferably 1: 7, can be used, and methylene chloride / carbon telrachloride by volume 1: 4 - 1: 7. Preferably 1: 5, and methanol / water in the volume ratio 2.2: I -24: I., preferably 2.3: 1, can be used.