PL171760B1 - Method of obtaining meproscilarine - Google Patents

Abstract

1. A method of obtaining meproscylarin from proscylaridine, consisting in protection the hydroxyl groups at the 2 'and 3' positions of the proscylaridine, the methyl group hydroxyl in position 4 'and deprotection of hydroxyl groups in positions 2' and 3 ', characterized in that the hydroxyl groups in the 2 'and 3' positions are protected with a benzylidene group, and after methylation at the 4-position, the protecting groups are removed by treatment with acid Lewis in an alcoholic solution.

Description

The subject of the invention is a method for the preparation of meproscylarin from proscyllaridine. Meproscylarin is the 4'-methyl ether of proscylaridine bufadienolide glycoside and finds use as a cardiac glycoside in the treatment of various forms of heart failure.

There is known from the German patent No. 1,910,207 a method for the preparation of meproscylarin from proscylaridine, which consists in O-methylation of proscylaridine in the 4 'position with the use of known methylating agents used for sugar methylation. The yield of such a reaction is low due to the low selectivity of methylation. There is also known from the German patent description No. 2,301,382 a method for the preparation of meproscylarin, consisting in the protection of the hydroxyl groups in the 2 'and 3' positions of proscyllaridine with an isopropylidene or orthoester group, selective methylation of the hydroxyl group in the 4 'position and subsequent removal of the protecting group by heating with an aqueous solution of mineral acid.

Due to the sensitivity of meproscylarin to acidic reaction conditions, deprotection of the aqueous acid solution leads to the formation of undesirable by-products, hindering product isolation and reducing yield.

A new method was developed to protect the hydroxyl groups in the 2 'and 3' positions of proscylaridine and to remove these groups after completion of the reaction under mild conditions, not requiring the use of aqueous acid solutions.

The process according to the invention consists in protecting the hydroxyl groups in the 2 'and 3' positions of the proscylaridine with a benzylidene group or with a benzylidene group substituted in the 4-position of the phenyl ring with lower alkyl or lower alkoxy, which is removed after a known methylation reaction in the 4 'position acting with Lewis acid in an alcoholic solution.

Preferably, iron (III) chloride is used as the Lewis acid, but other Lewis acids such as iron (III) bromide, aluminum chloride, zinc chloride, zinc bromide, tin (IV) chloride, boron trifluoride and others may also be used successfully. .

By lower alkyl or alkoxy "is meant alkyl and alkoxy groups having 1 to 3 carbon atoms. The benzylidene protecting group may be substituted at the 4-position of the phenyl ring with such substituents as, for example, methyl, methoxy or ethoxy.

The 2 ', 3' -benzylidene derivative of proscylaridine is obtained by reacting proscylaridine with benzaldehyde or an appropriately substituted benzaldehyde under acid catalysis with azeotropic water removal. The 2 ', 3' -benzylidene derivative can also be obtained by reacting proscylaridine with the appropriate acetal of benzaldehyde or an appropriately substituted benzaldehyde, for example acetal

171 760 dimethyl or diethyl, carried out in DMF solution against pyridine p-toluenesulfonate.

The deprotection reaction can be carried out in an alcoholic solvent such as methanol, ethanol, isopropanol.

The methylation is carried out according to known methods, customary for the preparation of O-methyl sugar derivatives, by treatment with methyl iodide in the presence of alkaline earth metal hydroxides and oxides, alkali metal hydrides and alkoxides and with silver oxide. The methylation reaction can also be carried out with dimethyl sulfate. Aprotic organic solvents such as DMF, acetone, tetrahydrofuran, dioxane, dimethyl sulfoxide, most preferably DMF are used as the solvent.

By the process according to the invention, meproscylarin with a high degree of purity is obtained. The product is easy to isolate without the use of column chromatography as a purification operation, which is only used in the preparation of 2 ', 3'-benzylidene-4'-O-methylproscylaridine.

Example.

A) 2 ', 3' -O-Benzylideneproscyllaridine

Proscylaridine (3.2 g, 6.04 mmol) was dissolved in 15 ml of slightly warmed DMF, benzaldehyde dimethyl acetal (2.28 g, 15 mmol) and 300 mg pyridine p-toluenesulfonate were added. The flask with the reaction mixture was connected to a rotary evaporator and the reaction was carried out at a temperature of about 50 ° C and a pressure of about 20-30 mm Hg (2.7 kPa-4.0 kPa), distilling the formed methanol. The mixture was diluted with ethyl acetate (100 ml), washed 3 x with water, then brine, and dried with MgSCO. After evaporation, the residue was used directly for the next step.

B) 2 ', 3' -O-benzylidene-4 '-O-methylproscylaridine

The product of step (A) was dissolved in 25 ml of DMF and 3 g of freshly prepared silver oxide Ag2O and 4 ml of methyl iodide were added. The reaction mixture was stirred for 8 hours at room temperature. It was then diluted with a mixture of ethyl acetate and ethyl ether (1: 1, v / v), the precipitate was filtered off and washed 3 x with water, then dried with MgSO. After evaporation, chromatography (flash) on silica gel, eluting the column with hexane-ethyl acetate 7: 3, yielding 3.1 g of product (yield after steps A and B 81.3% O).

C) Meproscillarin

2 ', 3'-O-Benzylidene-4'-O-methylproscyllaridine (0.51 g, 0.81 mmol) was added to a solution of FeCl3 (0.262 g, 1.6 mmol) in 26 ml of methanol and allowed to stand at room temperature for 24 hours. Half of the methanol was evaporated on the evaporator, the residue was diluted with 50 ml of ethyl acetate and washed twice with water, once with saturated NaHCO3 solution, once with brine and dried with MgSO4. A few ml of ethyl acetate were added to the semi-crystalline evaporation residue and after about 1 hour it was filtered off to give 0.3 g of product. An additional 0.02 g of product was obtained from the filtrate after concentration and crystallization. Total yield 0.32 g of the product (total yield after 3 steps 59.5%), containing approx. 1.5% (HPLC) of proscylaridine. Melting point 202-212 ° C.

By carrying out the reaction at 30 ° C (water bath) after 4 hours, no starting material was detected (TLC), and little more by-products. Crude product yield over three steps 59.5%.

171 760

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Claims (2)

Patent claims 1. A method for the preparation of meproscyllarin from proscylaridine, which consists in protecting the hydroxyl groups in 2 'and 3' positions of proscylaridine, methylating the hydroxyl group in the 4 'position and deprotecting the hydroxyl groups in the 2' and 3 'positions, characterized in that the hydroxyl groups in the 2' and 3 'positions are 'and 3' are protected with a benzylidene group, and after methylation at the 4 'position, the protecting groups are removed by treatment with Lewis acid in an alcoholic solution. 2. The method according to p. The process of claim 1, wherein the Lewis acid is iron (III) chloride.