SU406346A1 - METHOD OF OBTAINING GLUCOSIDES - Google Patents

Description

This invention relates to a method for the preparation of exogenous glucosides with high physiological activity.

A known method for producing alkylidene derivatives of 4-demethylepipodophyllotoxin p-D-glucoside by reacting a glucoside with a carbonyl compound of the general formula Rj.RjC O, where RI is hydrogen, R2 is lower alkyl, or with the corresponding acetals or ketals in the presence of a catalyst — Lewis acids.

The proposed method of producing glucosides of the general formula

... -he

where RI is GI is C3-alkyl,

consists in the interaction of 4-benzyloxycarbonyl-4-emethyl epinodophyllotoxin

15

20

from 4.6: 0-alkylideneglucopyranose

general formula

25

WITH)

thirty

where Ri is as indicated above; R2 is formyl or acetyl, in the presence of boron trifluoride etherate in an inert organic solvent medium, followed by cleavage of protective groups by known techniques.

For the protection of hydroxyl soils in gluconnranosis, formlope groups are used, which are cleaved under milder conditions.

The yield of the obtained alkylidene derivative is 4-demethlepipodophyllotoxin-p-1 glucose, 72% (in the known method 427o) The high yield of the target product is due to the fact that the stage of condensation of 4-demethylenipodophillotoxin-p-glucoside with a carbonic compound is excluded.

The reaction is usually carried out at (- 15) - (-25) ° C in dichloroethane.

Protective acetyl groups against the compound

about

SOOSN-g

CHbCOO, SN ,, СОО

CHsO

are separated mildly by treatment with a mixture of zinc acetate and sodium acetate in a mixture of methanol and tetrahydrofuran, followed by hydrogepolysis in the presence of a nalladium catalyst to remove the carbobenzoxy group.

It is advisable to hydrogenate at low pressure and a temperature of 20-40 ° C in the presence of 0.5 weight. % palladium on coal or sulphate ba, ri. As solvents, it is better to use alcohols, for example methanol or ethanol, with the addition of 10-50 vol. % acetone.

To remove protective formyl groups from compounds

zinc acetate in methanol can be used and then hydrogenolysis of the compound

.-T-J

Roo

In the presence of a palladium catalyst.

Obtained by reacting aliphatic aldehyde with glucose in the presence of acidic catalyst 4,6-O-alkylidene glucopyranose of the total formula

BUT

where R has the above meaning, is converted into salt with caustic soda, which in an anhydrous inert solvent is subjected to an exchange reaction with benzyl formate, the resulting compound of the general formula R, -T-0-1 O-T o. II / But, (-o-CH2L / but where RI, as indicated above, is treated with derivatives of acetic or formic acid, for example, their anhydride, in the presence of pyridine, the compounds of the general formula 0-, -rJ-0 -20. O-C O-CHg -) OH2, where RI and RZ are as defined above, are subjected to hydrogenolysis in the presence of a palladium catalyst in a dry a Only freshly prepared palladium obtained by reduction of palladium chloride (PdCb) is suitable for hydrogenolytic cleavage of the benzyloxycarbonyl group. Example 1. 4 - Demethylepipodophyllotoxin-p- / -ethylidene glucoside. 160 g of 4-benzyloxycarbonyl-4-demethylepipodophyllotoxin is dissolved by heating in 45 ml of dichloroethene, cooled to 20 ° C, 17.5 g of 4,6-O-ethylidene-2,3-di-Oacetyl-p-O- are added glucopyrazia, stirred at 20 ° C until dissolution, cooled to -18 ° C in the absence of moisture, 10.5 ml of i6opa trifluoride etherate was added dropwise with a stirring for 3 minutes while stirring and stirred at -18 ° C for 40 minutes. While cooling and stirring, a mixture of 10.5 ml of absolute pyridine and 100 ml of ethylene chloride is added dropwise, washed with 4 X 50 ml of water, dried the organic phase over sodium sulfate, evaporated in vacuum and the residue is dried in high vacuum at 60 ° C. Crude the product is dissolved in 60 ml of hot ethanol, the solution is added dropwise to 240 ml of water with stirring and cooling with ice, stirred for 20 minutes, the white precipitate is filtered off with suction, washed with 50 ml of a mixture of water and ethanol (4: 1) and dried under high vacuum at 70 ° C. After recrystallization from methanol two times, was pure 4-benzyloxycarbonyl-4-demetilepipodofilloto Ksin- | 3-1) - 2,3 di-0-acetyl-4, 6-0-etilidenglyukozid, mp.. 230 ° C; - 60.4 ° (c 1.054, chloroform). To a solution of 18.6 g of 4-beisyloxycarbonyl-4-methylisepipodophyllotoxin-p-D-2, 3-di-O-acetyl-4, 6-0-ethylidene-glucose IxCh in a mixture of 120 ml of methanol and 30 ml of absolute tetrahydrofuran was added 2.2 g of anhydrous acetate zinc and 0.8 g of anhydrous sodium acetate, heated under reflux for 4 hours, 20 ml of solvent are distilled off, 10 ml of absolute tetra are added. hydrohydrofuranium and heated for 20 hours. Concentrated to 70-80 ml, heated for 7 hours with an o6paTHFjiM condenser, 2 ml of acetic acid are added to the solution, evaporated in vacuo at 40 ° C, the residue is dissolved in 150 ml of chloroform, washed with 4x20 ml of water, dried over sodium sulfate, evaporated under vacuum and chromatograph the residue on silica gel, eluting with chloroform with 2-3% methanol. First, the incompletely deacetylated mass is isolated, and then the fraction consisting of a mixture of 4-benzyloxycarbonyl4-demethylenipodophyllotoxin- (3-) - ethylidene glucoside and 4-demethylepipodophyllotoxin-pD-ethylidene glucoside. The fractions obtained are chromatographed on silica gel plates, eluting with chloroform with 3% methanol. For the manifestation, a solution of 0.2% cerium (IV) sulfate in 50% acetic acid is used and heated at PO-130 ° C. To remove the benzyloxycarbonyl group, the fraction was dissolved in 100 ml of an acetone-ethanol (1: 1) mixture and hydrogenated in the presence of 2 g of a palladium catalyst (5% palladium on carbon) at 20 ° C and atmospheric pressure. After hydrogenolysis, the catalyst is filtered off, washed with a mixture of acetone - ethanol (1: 1) and the filtrate is evaporated in vacuo. The residue is recrystallized four times from ethanol by adding ethyl acetate, and 4-demethyl-epipodophyllotoxin-p — D-ethylidene glucoside is obtained, m.p. 253-255 ° C (after drying under high vacuum at 110 ° C). After crystallization from methanol, m.p. 236-253 ° C; - 111,0 ° (with 1,046, chloroform). To synthesize the starting 4,6-O-ethylidene-2,3-diO-acetyl-p- / 3-glucopyranose to 102 ml 2 n. caustic soda, cooled to 0 ° C, is added 41.6 g of 4.6-0-ethylidene - /) - glucopyranose, stirred to dissolve, add 1000 ml of ethanol: ether (3: 2), stir for 15 minutes cooled with ice, filtered, washed with 200 ml of ethanol and 300 ml of ether, dried in high vacuum at room temperature and get the sodium salt of 4,6-O-ethylidene - /) - glucopyranose. To a suspension of 40 g of sodium salt of 4,6-O-ethylidene-) -glucopyranose in 750 ml of absolute and alcohol-free chloroform was added 40 g of 75% benzyl formate, stirred for 16 hours in the absence of moisture at 20 ° C, added 160 ml of isopropanol, stirred for 5 minutes, add 200 ml of a mixture of chloroform-isopropanol (4: 1) and wash with OX X with 100 ml of water. After drying over sodium sulfate, the organic phase is evaporated in vacuo and the residue of SX is extracted with 150 ml of ether. The ether-insoluble residue is dissolved in 900 ml of hot ethyl acetate, concentrated to 300 ml in a weak vacuum, recrystallized twice from ethyl acetate, and 4,6-O-ethylidene-1-O-benzyloxycarbonyl-p- /) -glucopyracio is obtained in the form of needles t. 168-169 ° C; -27.7 ° (c 1.044, chloroform). To a mixture of 50 ml of absolute cyridine and 50 ml of acetic anhydride was added 42.5 g of 4,6-O-ethyl 11-1-0-benzyloxy "arbonyl-p - D glucopyranose, kept for 15 hours at first with cooling ;; cold water; and then at 20 ° C. After evaporation in vacuum, the residue is dissolved in three portions of benzene in 100 ml each, the benzene is evaporated in vacuo and the residue is crystallized in 100 ml of acetone, and 30 ml of ether are added. Crystallization from acetone-ether-pentane gives pure 4,6-O-ethylidene-1-0-benzyloxycarboiyl-2, 3-O-acetyl-p-O-glucopyranose, t. Pl. 161 ° C; fccfo -46.1 ° (; 95, chloroform). 500 mg of PdCb are dissolved in 50 ml of water, 100 ml of methanol are added, hydrogenated at 20 ° C and atmospheric pressure, the upper layer of the solution is decanted from the precipitated naladium, the palladium is carefully freed from the acid, and the methanol is removed by washing 3X150 ml of dry acetone. The Ps-luchenyna palladium catalyst is suspended in 250 ml of dry acetone, 25.5 g of 4,6-O-ethylene-1-0 benzyloxycarbonyl-2, 3-di-O-acetyl - | -O-glucopyranose and hydrogenated for 1 hour at 20 ° C and atmospheric pressure. After filtering the catalyst and washing it with 100 ml of dry acetone, the filtrate is evaporated in vacuum at 35 ° C (bath temperature), the residue is dried for 1 hour at 30 ° C in high vacuum, treated with 50 ml of diisopropyl ether at 30-35 ° C and recrystallized from a mixture an, eton - peptan. Get 4,6-O-ethylidene-2,3-di-O-acetyl- | 3-D - glucopyranose, so pl. 109-111 ° C; ar -35.9 ° C (s-1,006, chloroform). Example 2. 4 - Demethylepipodophyllotoxin-p-L-ethylidene glucoside. 8.0 g of benzyloxy ' arbonyl-4-demethyl-epipopophyllotoxin is dissolved by heating in 25 ml of dichloroethane, cooled to 20 ° C, 7.00 g of 4,6-O-ethylidene-2,3-di-0-formyl - - - glucopyranose and stirred until dissolved. In the absence of moisture, the mixture is cooled to -15 ° C, while stirring for 5 min, 5.5 ml of boron trifluoride etherate are added dropwise, stirred for 45 min at (-15) - (-18) ° C, and the mixture is added dropwise 5.5 ml of absolute pyridine and 100 ml of dichloroethane. After washing with 4X50 ml of water, the organic phase is dried over sodium sulfate, evaporated in vacuo, the residue is poured onto 200 ml of hot methanol, 1 g of anhydrous zinc acetate is added and the mixture is heated for 3 hours with a reflux condenser; observed the formation of a crystalline precipitate. The reaction solution is evaporated with the precipitate in vacuo, the residue is dried briefly under high vacuum at 60 ° C and treated with 100 ml of chloroform, 30 ml of water and 1 ml of acetic acid. The organic phase is washed with 2 X 50 ml of water, dried over sodium sulfate, evaporated in vacuo, the residue is dried under high vacuum at 60 ° C and treated with 60 ml of warm ethanol. After separating the insoluble fraction, the filtrate is evaporated in vacuo, the residue is crystallized from ethyl acetate, pentane is added, the crystallized solution is dissolved in 50 ml of chloroform, filtered through 5 g of silica gel, additional 50 ml of chloroform is washed and the combined filtrates are evaporated in vacuo. After the residue is crystallized twice from isopropyl acetate, pure 4-benzyloxycarbonyl-4 demethyl-epipodophyllotoxin-p-Z) - ethylidene glucoside is obtained, m.p. 156-157 ° C; afo -84.6 ° (c 1.040, chloroform). To a solution of 5.0 g of 4-bepsyloxycarbonyl-4-emethyl epidophyllotoxin-pD - ethylidene glucose in 100 ml of a mixture of acetone - ethanol (1: 1) add 0.5 g of palladium catalyst (5% palladium on carbon) and hydrogenate at 20 ° C and atmospheric pressure. At the end of the hydrogenolysis, the catalyst is separated, washed with acetone-ethanol (1: 1) and the filtrate is evaporated in vacuo. After the residue is crystallized twice from acetone-ethyl acetate, pure 4-demethyl-epipodophyllotoxin-p- (1) ethylidene glucoside is obtained with the same concatenation as the compound obtained in Example 1. For the synthesis of the initial 4,6-0-ethylidene-2,3 -diO-formyl-p-) -glucopyranose for 20-30 minutes in 48 ml of acetic anhydride while stirring and cooling with ice in the absence of moisture, 38 ml of anhydrous formic acid are added dropwise, and the temperature should not exceed 25 ° C, and is kept for 4 hours at 20 ° C. Similarly, when hydrogenating, as described above, 24.0 g of 4,6-O-ethylidene-1-O-benzyloxycarbonyl-2, 3-di-O-formyl-p-1 - glucopyranose, get 4,6-0-ethylidene -2,3-di-0-formyl-O-glucopyranose, which is crystallized from a mixture of dry acetone - ether - pentane and then twice from a mixture of dry acetone - ether. Double t. Pl. 109 ° -114 ° С / 135-137 ° С; af -37.9 ° (c 1.052, chloroform). Analogously to examples 1 and 2, 4-demethyl-epipodophyllotoxin-p-D — propylidene glucoside, colorless crystals, m.p. 178-182 ° C; and about - 107,2 ° (s--. 0,558, chloroform); 4-demethylepipodophyllotoxin-p - D - butydidene glucoside, t. Pl. 170-176 ° C; afo - Ш0.1 ° (с 0.754, chloroform); 4-demethylepipodophyllotoxin-p-D - isobutylidene glucoside, t. Pl. 181-185 ° C; - -96.9 ° (c 0.722, chloroform); 4-demethylepipodophyllotoxin-p - D - beer alilidene glucoside, double t. Pl. 162-165 ° C / / 173-177 ° C; - 96.5 ° (c 0.775, chloroform); 4-demethylepipodophyllotoxin-p-1) - pentylidene glucoside, t. Pl. 234-251 ° C; and in -101,9 ° (with 0,710, chloroform); 4-demethylepipodophyllotoxin-p-O- (2-methylpentylidene) -glucoside, so pl. 143-150 ° C; Jaf -100.9 ° C (1.004, chloroform); 4-demethylepipodophyllotoxin - p - /) - hexylidene glucoside, so pl. 219-238 ° C; and D is -158.3 ° (, 757, pyridine). The subject of the invention is a method for producing glucosides of the general formula 20 25 40 45 wherein RI is GI-Cs-alkyl, characterized in that 4-benzyloxycarbonyl-4-demethylepipodophyllotoxin is reacted with 4,6-O-alkylidene glucopyranose of the total formula where RI has the above meaning; R2 is formyl or acetyl, in the presence of boron trifluoride etherate in an inert organic solvent medium, followed by cleavage of m protective groups and the target product is isolated with known techniques. 2. Method of claim 1, wherein the protective acetyl groups are cleaved with a mixture of zinc acetate and sodium acetate in methanol-tetrahydrofuran mixture, followed by removal of the carbobenzoxy group during hydrogenolysis in the presence of a palladium catalyst. 3. A method according to claim 1, wherein the protective formyl groups are cleaved with zinc acetate in methanol, followed by removal of carobenzoxy groups during hydrogenolysis in the presence of a palladium catalyst.