DE2115408C3 - Process for the production of cardiotonic glycosides from aglycon and 1-halogen sugar - Google Patents

Description

in which R _{1 is} an optionally substituted glycoside radical, R _{2 is} an aldehyde or methyl group, R ₃ , R ₄ and R _{5 are} a hydrogen atom or a hydroxyl group, R _{6 is} a butenolide or a-pyrone ring, by reaction of a steroid aglycons of the general formula II

HO

(Π)

wherein R ₂ , R ₃ and R _{6 have} the meaning given above and R ₄ and R _{5 represent} a hydrogen atom, a hydroxyl group or a lower acyloxy group, with an O-acylated 1-halosugar in an inert solvent with removal of the water of reaction formed by means of azeotropy Distillation and saponification of the acylated glycosides obtained, characterized in that the reaction is carried out in the presence of silver carbonate finely divided on zeolite.

The present application relates to a process for the production of cardiotonic glycosides general formula I.

HO

35 wherein R ₂ , R ₃ and R _{6 have} the meanings given above and R ₄ and R _{5 represent} a hydrogen atom, a hydroxyl group or a lower acyloxy group, with an O-acylated 1-halosugar in an inert solvent with removal of the water of reaction formed by means of azeotropic distillation and saponification of the acylated glycosides obtained, characterized in that the reaction is carried out in the presence of silver carbonate finely divided on zeolite.

It is known from the relevant literature that the sugar residue is based on the Genin part biological effect of cardiac glycosides, especially with regard to their pharmacodynamic properties, can influence in a therapeutically desirable or undesirable sense. An in-depth pharmacological testing of the influence of the sugar residue has so far mostly failed because that the glycosides of interest are not available from natural sources or are only available in small quantities was. There has therefore been no lack of attempts to use natural or synthetic cardiac glycosides To obtain partial synthesis from more easily accessible aglycones on a larger scale. The well-known Glycoside synthesis according to Königs-Knorristin numerous Variants used with varying success for the partial synthesis of cardenolides and bufadienolides been. A yield of over 50% has only been achieved in a few exceptional cases. The difficulties probably stem from the fact that, due to the unstable nature of the permanent hy-

droxyl group the formation of undesirable, because inactive, anhydrogenins to reduce the yield lead (see the review by W. W. Z or bach et al, Adv. Carbohydrate Chem. 21, 273 [1966]). So results for example the Königs-Knorr reaction of a-L-acetobromrhamnose with strophanthidine in the Modification according to Meystre and Miescher with subsequent saponification a yield of 44% Strophanthidin-a-L-rhamnopyranosidi-convailatoxin; HeIv. 33, 1541 [1950]), while the corresponding Implementation with a-D-acetobromoglucose according to HeIv. 40, 284 (1957) strophanlhidine-ii-D-glucopyranoside only obtained in varying yields (6 to 35%). Even the modification of the process according to V. T. C h e r η ο b a i (Z. obä. Chira. 14 [1964], 1014; Adding calcium oxide) does not bring any decisive improvement. The Hg (CNV method according to Helferich proved to be successful in individual cases (e.g. in the presentation of Evomonosid, J. org. Chem. 27 [1962], 1766; Yield: 44% of the crude product), but seems to be based on previous experience not to be generally applicable, see W. W. Z ο r b a c h, 1. c). A noticeable increase in yield is observed, however, if, according to German Offenlegungsschrift 1 933 090, the reaction mixture Small amounts of basic substances such as calcium carbonate are added compared to this process however, the present process according to the invention is characterized by comparable yields Glycosides are characterized by considerably shorter reaction times. Avoidance of basic additives also excludes the risk of isogenins in the process claimed by us, which could complicate the isolation of the desired glycosides. Furthermore, the inventive Process a smaller excess (usually only twice the molar amount) 1-halogen sugar, which is a decisive economic advantage, especially with the rarer sugars offers.

The process according to the invention must be regarded as surprising, since it is used as a condensing agent preferably used reagent supercarbonate on zeolite according to CR. 267,900 (1968), as an excellent one Oxidizing agent for the oxidation of alcohols, especially steroid alcohols, is used. An oxidation the 3/3 hydroxyl group of the aglycones used is, however, in the process claimed here not observed.

Cardenolides and bufadienolides are suitable as aglycones for the partial synthesis, such as in particular the easily accessible aglycones strophanthidin, digitoxigenin, 12-O-acetyl-digoxigenin, 16-O-acyl-gitoxigenin, gitaloxigenin, oleandigenin, Hellbrigenin and others

Poly-O-acylated chlorine, bromine or iodose sugars, such as z. B. Acetochlorglucose, Acetobromoglucose, Acetobromrhamnose, Acetobrommannose, Benzobromrhamnose, Benzochlorrhamnose, Acetobromxylose, Acetobromallose, p-Nitrobenzochlorrhamnose, also N-acyl or N-phosphorylamino-1-halogen sugar.

Particularly suitable heavy metal salts are carbonates, oxides and cyanides of the elements of the first and second subgroups of the periodic table such as Ag ₂ CO ₃ , Ag ₂ O, HgCO ₃ , CdCO ₃ , HgO, Hg (CN) ₂ , which are freshly precipitated on zeolite . Freshly cleaned kieselguhr with the predominant particle size 20 to 45μ is preferred as the zeolite Ratio 2: 1 to 1: 4, preferably about 1: 1, suspended and mixed with the equivalent amount of sodium carbonate. After filtering and washing neutral, the powder obtained is in vacuo at

ίο 35 to 40 ⁰ C dried

The reaction according to the invention is advantageously carried out in such inert solvents according to the method of Meystre and Miescher for the synthesis of. Steroid glycosides also act as entrainers, which are released during the implementation Constantly remove water by azeotropic distillation. Suitable are e.g. B. chloroform, benzene, toluene, Dichloroethane, trichloroethane, benzene-dioxane, toluene-dichloroethane. Accordingly, the reaction is expedient at the boiling point of the relevant Solvent made.

To carry out the reaction, the aglycon is azeotroped from any adhering crystal solvent Freed from distillation with a suitable solvent, dissolved in an inert solvent or suspended and mixed with the heavy metal salt - zeolite reagent. The reaction mixture will brought to the boil. To remove the last traces of moisture, first some Milliliters of solvent are distilled off before the solution of the halogen sugar is added. In advantageous One can also proceed in such a way that the aglycone is dissolved in a suitable solvent and after adding the Zeoliih mixture by evaporation in vacuo in finely divided and therefore a form favorable for the reaction. The residue is then suspended in the reagent and after heating to boiling, added the halogen sugar.

A two to four-fold excess of halogen sugar and a five to ten-fold excess are used of heavy metal salt.

The water formed during the reaction is continuously removed by means of azeotropic distillation To keep the reaction volume constant, fresh solvent is used in accordance with the rate of distillation admitted.

As the reaction is monitored by thin-layer chromatography shows, the reaction proceeds

almost completely within 15 to 60 minutes.

. After filtering and evaporating the solvent, the acyl glycoside formed can be detected by chromatography isolate on aluminum oxide or silica gel. Since this separation operation because of in excess existing sugar derivatives is very troublesome, it is expedient to proceed in such a way that the Reaction mixture is saponified in toto, and that then the free glycosides by direct crystallization, Extraction by means of organic solvents or chromatography from the polar, water-soluble ones Sugars are separated. The saponification takes place according to known methods by means of aqueous alcoholic potassium bicarbonate solution or methanolic ammonia.

The products of the process have valuable pharmacological properties as positive inotropic cardiac glycosides and are used to treat heart failure.

table

Comparison of the molar ratios of halogen sugar to aglycone and the response times of P 21 15 408.5 and German Offenlegungsschrift 1933 090

Glycoside

Example no.

MoI ratio

reaction time (Hours.)

German Offenlegungsschrift 1 933 090 Example no.

Molar ratio

reaction time

(Hours.)

Digitoxigenin ^ iD-glucoside ...
Digitoxigenin-aL-rhamniosid ..
Strophanthidin-aL-rhamnoside
Digitoxigenin - /? - D-galactoside ..
Strophanthidin-ß-D-galactoside
Strophanthidin - /? - D-glucoside ..

1.73
2.00
1.78

2.00

1.0

0.75 ^ 1.0

0.5- ^ 1.0

1.0

1
2
3
4th

3.2

4.25

3.5

3.6

2.95

4.5

4.0

1.75

5.75

2.0

.Example 1
Strophanthidm-aL-rhamnopyranosid (convallatoxin)

25th

7.20 g of silver on zeolite (corresponding to 3.46 g of silver) and 1 g Strophanthidin are suspended in 50 ml of dichloroethane and heated to 120 ⁰ C. With vigorous stirring, a solution of 1.8 g of acetobromrhamnose in 10 ml of dichloroethane is then added dropwise over the course of 15 minutes, the solvent being allowed to distill off at the same time. After the addition is complete, the reaction mixture is kept boiling for a further 15 to 45 minutes. The addition of solvent ensures that the reaction volume remains approximately constant. Analysis by thin layer chromatography on silica gel (mobile phase: chloroform / methanol 9: 1, v / v) shows that after this reaction time no more genin is present. After filtration and evaporation, the residue is dissolved in 50 ml of methanol, and 20 ml of methanolic ammonia solution saturated at 0 ° C. is added. The solution is left to stand for 18 hours at 5 ° C., evaporated and, by crystallization from methanol / water, 733 mg (54% of theory) of pure convallatoxin, melting point 225 to 226 ° C. Chromatography of the mother liquor residue on silica gel gives another 274 mg of convallatoxin , increasing the overall yield to 74%.

The synthetically obtained product turns out to be identical to that obtained from the Convallaria drug natural convallatoxin.

Example 2
Digitoxigenin-aL-rhamnopyranoside (Evomonoside)

374 mg of digitoxygen and 5.70 g of silver carbonate on zeolite (corresponding to 2.75 g of silver carbonate) are suspended in 50 ml of absolute benzene and ω heated to 125 ° C in a protective gas atmosphere. The mixture is left with vigorous stirring for 15 minutes instill a solution of 0.822 g of acetobromorhamnose in 25 ml of benzene. The reaction mixture is held for a further 30 to 45 minutes after it has ended Addition at the boil, then allowed to cool, filtered, evaporated in vacuo, the residue is taken in 50 ml of methanol and mixed with 25 ml at 0 ° C

55

methanol saturated with ammonia gas. The solution is left to stand at room temperature for 18 hours and then evaporated in vacuo. The residue is taken up with a little methanol / water and concentrated in vacuo. The crude product which precipitates out (545 mg) is separated off from the solution. chromatographed on silica gel and crystallized from acetone benzene, melting point 215 to 230 ° C., yield: 312 mg (60% of theory).

Example 3
Strophanthidin - /} - D-glucopyranoside

2 g strophanthidin and 11.4 g of silver on zeolite (corresponding to 5.5 g of silver carbonate) are suspended in 50 ml of absolute dioxane, and 50 ml of benzene and heated in an inert gas atmosphere with vigorous stirring at 12O ⁰ C. As soon as the solvent boils, a solution of 4.08 g of acetobromoglucose in 25 ml of benzene is added dropwise over a period of 30 minutes. After the sugar has been added, the reaction mixture is kept boiling for a further 30 minutes. It is allowed to cool, filtered and evaporated in vacuo. The residue is taken up in 160 ml of methanol and ^{mixed with 40 ml of methanol saturated with ammonia gas at 0 °} C.. After standing at room temperature for 18 hours, the solution is brought to dryness. It is mixed with water and extracted first with chloroform and then with a chloroform / alcohol mixture (2: 1, v / v). Chromatography of the chloroform / alcohol extract on silica gel yields 1.704 g of thin-layer chromatography homogeneous strophanthidin-jS-D-glucopyranoside (61% of theory), which is umknstallisiert from isopropanol / ether, mp. 180 ⁰ C

C ₂₉ H ₄₂ O ₁₁ :
Calculated
found .

C 61.47, H 7.47, 0.31.06%;
C 61.24, H 7.41, O 31.15%.

Example 4

Digitoxigenin-jJ-D-glucopyranoside

374 mg digitoxigenin and 2.85 g silver carbonate on zeolite (corresponding to 1.37 g silver carbonate) are

suspended in 25 ml of absolute benzene and with a solution of 710 mg of acetobromoglucose in 7 ml of abs. Benzene added. With vigorous stirring in a protective gas atmosphere, the mixture is heated to the boil at a bath temperature of 120 to 125 ° C. It is allowed to distill slowly for 60 minutes with the dropwise addition of fresh solvent, nitrated after cooling to room temperature, evaporated in vacuo, taken up in 80 ml of methanol and, after the addition of 20 ml at ⁰ ° C. with ammonia gas

in saturated methanol overnight at room temperature. It is evaporated again and the residue is taken up in methanol / water. The crude product which precipitates on concentration in vacuo is chromatographed on silica gel for further purification. This gives 280 mg (52% of theory) digitoxigenin - /? - D-glucopyranoside homogeneous by thin-layer chromatography as a colorless crystalline material. Recrystallization once from chloroform / methanol gives 237 mg of product with a melting point of 242 to 247 ^° C.

Claims (1)

Claim: Process for the production of cardiotones Glycosides of the general formula I R ₁ -O R ₁ -O OH (I) is in which R _{1 is} an optionally substituted glycoside radical, R _{2 is} an aldehyde or methyl group, R ₃ , R ₄ and Rf are a hydrogen atom or a hydroxyl group, R _{6 is} a butenoed or a-pyrone ring, by reaction a steroid aglycon of the general formula II