RU2351604C1 - Method of producing 2,3-monoacetonide 20-hydroxyecdysone - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention refers to synthesis of biologically active substances, in particular specifically, to improved method of producing 2,3-monoacetonide 20-hydroxyecdysone of formula

found in very small amounts in some plants, e.g. Rhaponticum carthamoides. Method is implemented by interaction of 20- hydroxyecdysone (1.0 g, 2.08 mmole) and acetone with phosphomolybdic acid (PMA) added. As suspension is effected by mother compound in PMA acetone (0.3 g, 0.16 mmole), after 5 min homogenisation of reaction mixture is observed to be steamed by neutralisation with 0.1% sodium hydrocarbonate solution with following ethyl acetate and chromatography extraction of the end product, thus resulting in isolation of the end 2,3-monoacetonide 20- hydroxyecdysone of 32% yield.

EFFECT: method is highly selective and single-stage.

2 cl, 1 ex

Description

The invention relates to the synthesis of biologically active substances, in particular to the synthesis of ecdysteroids, specifically to the synthesis of 2,3-monoacetonide 20-hydroxyecdysone (I).

2,3-Monoacetonide I is present in very small amounts in some plant species, for example Rhaponticum carthamoides. [Ecdysteroids of the root bark of Vitex caescens. // Phytochemistry, 1997, 45, No. 6, 1149-1152].

Ecdysteroids are widespread in the animal and plant world and act as regulators of molting and metamorphosis of insects and crustaceans. Being non-toxic to mammals, these compounds and their analogues are of interest to medicine.

As a derivative of 20-hydroxyecdysone (II), selectively protected by 2,3-hydroxyl groups, 2,3-monoacetonide (I) is convenient for subsequent selective transformations of one of the most representative phytoecdysteroids II into ecdysteroids that are not widespread in nature. For example, in the synthesis of chidasterone 2,3-monoacetonide I was obtained by three-stage transformations of 20-hydroxyecdysone II [1] [Roussel P.G., Turner N.J., Dinan L.N. Synthesis of Shidasdterone and the Unambiguous Determination of its Configuration at C-22. // J. Chem. Soc. Chem. Commun., 1995, 933-934]. The reaction of 20-hydroxyecdysone II with phenylboronic acid in dimethylformamide (DMF) yielded 20,22-phenylboronate of 20-hydroxyecdysone (III). Interaction of III with 2,2-dimethoxypropane and TsOH in acetone yields 2,3-acetonide-20,22-phenylboronate of 20-hydroxyecdysone (IV). Treatment of IV with a 30% hydrogen peroxide solution in the presence of NaOH in tetrahydrofuran resulted in the selective removal of boronate protection and the production of 2,3-monoacetonide I, the total yield of which was 65% (Scheme 1).

Scheme 1.

The disadvantages of this method are multi-stage, the use of specific and expensive reagents, incomplete conversion of the starting compounds at each stage, which requires additional purification of the intermediate and final products.

The objective of the invention is to simplify the method of producing 2,3-monoacetonide 20-hydroxyecdysone.

An essential distinguishing feature of the proposed method, allowing to solve the problem, is the use of phosphoric-molybdenum acid in the reaction of 20-hydroxyecdysone II with acetone, followed by separation of the resulting product by column chromatography.

The possibility of obtaining compound I by reacting 20-hydroxyecdysone II with acetone in the presence of an acid seems very attractive. However, according to the known method [2] [Odinokov V.N., Galyautdinov I.V., Nedopekin D.V., Halilov L.M. Trifluoroacetylation and dehydration of acetonides 20-hydroxyecdysone. The synthesis of stachisterone B. // Izv. AN Ser. Chem. - 2003. - No. 1. - C.220-224] reaction of II with acetone in the presence of 0.1 mol% of phosphoric-molybdenum acid (PMA) leads to a mixture of (85:15) 2,3: 20,22-diacetonide (V) and 20,22-monoacetonide 20-hydroxyecdysone (VI):

Scheme 2.

When studying the interaction of 20-hydroxyecdysone II with acetone in the presence of PMA, it was found that in the interaction of a suspension of compound II and 7-8 mol. % PMA in acetone after 5 min, homogenization was observed and a green color appeared in the reaction mixture. By evaporation, neutralization with a 0.1% sodium hydrogen carbonate solution, followed by extraction of the target product with ethyl acetate and chromatography, 2,3-monoacetonide identical to (IR, UV, ¹ H and ¹³ C NMR) of 2,3-monoacetonide described previously in the above-mentioned 3- stage synthesis [1].

Scheme 3.

The undoubted advantage of the proposed synthesis is the one-stage process and the availability of reagents, which greatly simplifies the method of obtaining the target product.

An example implementation of the method. To a suspension of 1.0 g (2.08 mmol) II in 200 ml of acetone was added 0.3 g (0.16 mmol, 7.7 mol%) of phosphoric-molybdenum acid. The reaction mass was stirred at room temperature until the reaction mixture became homogeneous and turned greenish (~ 5 min). The reaction mixture was evaporated to a volume of ~ 25 ml, 15 ml of a 0.1% NaHCO ₃ solution were added and extracted with ethyl acetate (100 ml × 3). The extract was evaporated and chromatographed on a column with 40 g of SiO ₂ (eluent — CHCl ₃ -MeOH, 9: 1) to obtain 0.35 g (32%) of compound I, mp 135-137 ° C, [α] _D ²⁰ + 29.6 ° (c = 2.53, MeOH), IR, UV, ¹ H and ¹³ C NMR are identical to those reported in the literature [1].

Along with the target compound I, diacetonide V (yield 30%, mp 134-135 ° C, [α] _D ²⁰ + 39.0 ° (c = 1.1, CHCl ₃ )) and 20.22- were isolated from the total reaction product monoacetonide VI (yield 38%, mp 223-224 ° C, [α] _D ²⁰ + 58.0 ° (c = 0.9, CHCl ₃ )).

Claims (1)

The method of obtaining 2,3-monoacetonide 20-hydroxyecdysone formula I

from 20-hydroxyecdysone, characterized in that 20-hydroxyecdysone is reacted with acetone in the presence of 7.7 mol% of molybdenum phosphoric acid until the reaction mixture is homogenized and the solution turns green at room temperature for 5 minutes, followed by isolation of the target product famous tricks.