SU576938A3 - Method of preparing 8-aminomethylisoflavone derivatives or salts thereof - Google Patents

Description

at the boiling temperature of the reaction medium, followed by isolation of the target product in free form as a salt.

Chloromethylation is carried out by paraformalde1, chromium, and dry gaseous hydrogen chloride or formaldehyde and concentrated aqueous hydrochloric acid in the presence of a Lewis acid, for example, in the presence of dank chloride, aluminum chloride or tin chloride. Acetic or nropionic acid can be used as the reaction medium. The process is carried out at a temperature of 60-10 ° C, preferably nri85-95 ° C.

The resulting compounds of general formula III can be isolated by concentrating the reaction mixture and precipitating with concentrated hydrochloric acid.

The reaction with the amine is carried out at the boiling temperature of the reaction mixture. Preferably, lower alcohols, such as methanol, ethanol or nanol, or an excess of amine of general formula IV are used as the reaction medium. An excess of amine at the same time, as an acid acceptor, serves to bond your hydrochloric acid to form.

The compounds of general formula I form salts with inorganic and organic acids. Hydrochlorides, hydrosulphates, nicotistates, bitartrates, citrates, gluconates and lactates are most preferred.

Salts formed by compounds of the general formula I with inorganic or organic acids crystallize from water-containing solvents with absorption of water of crystallization.

Example. 50.4 g of 7 - labels of zof lavium syrup are suspended in 500 ml of glacial acetic acid and, after addition of 24.0 g of paraformaldehyde, are heated to 90 ° C. To the resulting clarified solution is added dropwise 1.5 g of zinc chloride in 50 ml of concentrated hydrochloric acid. The reaction mixture was stirred for another 2 hours at 90-95 ° C, then 1 g of activated carbon was clarified and filtered.

The filtrate is evaporated in vacuo to 100 ml. This residue is diluted with 20 ml of concentrated hydrochloric acid and then filtered after cooling with ice. The precipitate is washed with 80% acetic acid, and then it is dried in a vacuum. The resulting 51.8 g of crude product is recrystallized from boiling methyl alcohol. 7-methoxy-8-chloromethyl isoflavone is obtained, which melts at 146-148 ° C.

EXAMPLE 2: 15.0 g of 7 - methoxy - 8 chloromethylsoflavone are suspended in 150 ml of methanol, 8 ml are added to the suspension (3 - methylaminoethanol and the mixture is boiled for 3 hours. The reagents are transferred to the solution without residue. 450 ml water and after cooling, the precipitated n {) product is filtered off. It is washed with 20%

methanol and then dried. 15.2 g of 7-methoxy-B - (methyl -) 3 - oxystilamino) methyl isoflavone are obtained, which, after recrystallization from methanol, melts at 72-74 ° C.

EXAMPLE 3 To a suspension of 60.0 g of 7-methoxy-8-chloromethyl-isoflavone in 600 ml of methanol, 35 ml of morpholine are added and the mixture is boiled while being placed. Within 20 minutes, a clarified solution is obtained. This solution is boiled for three hours. The resulting weak yellow solution is poured into 2400 ml of water. After cooling, the precipitate is filtered off, washed with 20% aqueous methanol and then dried. El, 7 g of 7-methoxy-8-morpholinomethyl-isoflavone is obtained, which, after recrystallization from methanol, melts at 179-180 ° C.

Salts of 7 - methoxy - 8 - morpholinomethyl isoflavone.

7 - Methoxy - 8 - morpholinomethyl isoflavone hydrochloride

17.5 g of 7-methoxy-8-morpholinomethyl isoflavone are suspended in 160 ml of absolute methanol, and the suspension is boiled while stirring. To the mixture is added 5 ml of concentrated hydrochloric acid in 15 ml of methanol, and the substance without wasps: {Atka goes into solution. After boiling for 15 minutes, it is clarified at the boiling point with activated carbon and then filtered. The filtrate is diluted with 15 ml of benzene, then 2/3 of the solvent is distilled off at atmospheric pressure. The hydrochloric acid salt is crystallized by cooling; the remaining solution. The solution, cooled to -10 ° C, is filtered, the crystals are washed with methanol and then dried. 16.9 g of hydrochloride are obtained, which melts at 240-242 ° C.

7 - Methoxy - 8 - morpholinomethyl isoflavone nicotinate

14.0 g of 7 - methoxy - 8 - morpholinomethyl isoflavone are dissolved in 140 ml of absolute isopropanol at boiling point. A suspension of 5.0 g of nicotinic acid in 15 ml of isopropanol is added to the solution. The slightly yellow solution is boiled for 15 minutes and. then cooled, the product crystallizes out, which after cooling to -10 ° C is filtered off and washed with isopropanol. After drying, 18.3 g of nicotinate are obtained, which, after recrystallization from isopropanol, melts at 157-158 ° C.

EXAMPLE 4 56.0 g of 7-isopropoxy-isoflavone are dissolved with gentle heating in 560 ml of acetic acid. 24 g of paraformaldehyde is added to the solution and heated to 90 ° C. With stirring, 150 ml of concentrated hydrochloric acid containing 1.5 g of zinc chloride is added dropwise to the solution over 2 hours. After heating for one hour at 90-95 ° C, they are clarified with activated carbon, filtered while hot and evaporated in vacuum to 150-160 ml. The residue thus obtained is diluted with 20 ml of concentrated hydrochloric acid and crystallized by stirring.

cooling. After cooling with ice, the crystals are filtered off and washed with 80% acetic acid. After drying, 50.6 g of 7-isopropoxy-8-chloromethyl isoflavone is obtained, which melts at 125-126 C.g

And p-me R 5. 32.8 g of 7-isopropoxy-8 chloromethyl isoflavone are dissolved in heat with the addition of 20 ml of morpholine in 164 ml of absolute alcohol and boiled for three hours. The boiling JQ solution while stirring is very slowly poured into 700 ml of water. After cooling, the precipitated crystals are filtered off and washed with 20% aqueous alcohol. 37.7 g of 7 isopropoxy-8-morpholinomethyl-isoflavone are obtained, 5 which after recrystallization from methyl alcohol melts at 126-128 ° C.

Salts 7 - isopropoxy - 8 - morpholinomethylisoflavone.

7 - Isopropoxy - 8 - morpholinomethylisofla- 20 vonghydrochloride monohydrate

10.0 g of 7 - isopropoxy - 8 - morpholinomethyl xzoflavone is dissolved at boiling in 50 ml of absolute alcohol. A mixture of 2.8 ml of concentrated hydrochloric acid and 25 10 ml of absolute alcohol is added to the solution. The mixture is boiled for 30 minutes, clarified with activated carbon, filtered and crystallized by cooling. The hydrochloride obtained is washed with 96% alcohol. 10.1 g of hydrochloride monohydrate are obtained, which melts at 223-224 ° C.

7 - Isopropoxy - 8 - morpholinomethyl isoflavone hydrosulfate

To a warm solution of 10.0 g of 7 - isopropoxy - 8 morpholinomethyl isoflavone in 40 ml of methanol, 1.45 ml of concentrated H2SO4 (specific weight 1.84) and 10 ml of methanol are added. The mixture is boiled for 15 minutes. The product begins to precipitate already at the boil. The mixture is cooled with stirring, then cooled with ice, filtered and the filtered product is washed with absolute methanol. After drying at 60 ° C, 9.9 g of hydrosulfate is obtained, which melts at 228-230 ° C.

7 - Isopropoxy - 8 - morpholinomethyl isoflavonicnicotinate45

10.0 g of 7 - isopropoxy - 8 - morpholinomethyl isoflavone are dissolved in hot form in 140 ml of isopropanol. A solution of 3.5 g of nicotinic acid in 10 ml of isopropanol is added to this solution. After boiling for 15 minutes, 30 minutes at 50, heating to boiling is clarified with activated charcoal, and then filtered. The product crystallized by cooling to -10 ° C is filtered and washed with isopropanol. After drying in a vacuum eccato, 11.5 g of nicotinate are obtained, which melt at 133-134 ° C.

If nicotinate 7 - isopropoxy - 8 - morpholinomethyl isoflavone is recrystallized from a multiple amount of 85% isopropyl alcohol, then the compound absorbs 1 mol 60

crystallization water and retains it even when dried in a desiccator. Salt melts TC at 106-108 ° C.

7 - Isopropoxy - 8 - morpholinoisoflavonbitartrate hydrate

10.0 g of 7 - isopropyl - 8 - morpholinomethyl isoflavone are dissolved in hot form in 40 ml of isopropanol. While stirring, a suspension prepared from 4.0 g of tartaric acid and 10 ml of isopropanol is added to the solution. After a few seconds, intensive crystallization of the product begins. The mixture is boiled for 15 minutes, cooled and filtered, and the crystals are washed with isopropanol. 13.3 g of bitartrate is obtained, which melts at 184-186 ° C.

7 - Isopropoxy - 8 - morpholinomethyl isofla-citrate hydrate

10.0 g of 7-isopropoxy-8-morpholinomethyl-isoflavone are dissolved at boiling in 50 ml of 85% isopropanol. A suspension of 6.5 g of citric acid in 15 ml of 85% isopropanol is added to the solution. 10 ml of anhydrous benzene was added to the solution, which had become completely transparent after 15 minutes. The remaining solution is clarified with activated carbon, then filtered and stirring, crystallized. After ice-cooling, the precipitated product is filtered, washed with isopropanol, and then dried. 14.1 g of salt is obtained, which melts at 151 -153 ° C.

7 - Isopropoxy - 8 - morpholinomethyl isoflavone gluconate

10.0 g of isopropoxy-8-morpholinomethyl isoflavone are dissolved in heat in 50 ml of anhydrous isopropanol. 10 ml of a 50% gluconic acid solution is added to the solution and the mixture is then boiled for 30 minutes. After thorough cooling, the product is filtered and washed with chilled (ice) isopropanol. After drying at 60 ° C, 15.5 g of white crystals melting at 131-1133 ° C are obtained.

EXAMPLE 6 20.0 g of 7-isopropoxy-8-chloromethyl eoflavone and 16 ml / 3-methylamino-ethanol are boiled for 6 hours with refluxing in 100 ml of absolute ethanol. Then the pale yellow solution is clarified with activated carbon, filtered and evaporated to dryness in vacuo. 31.0 g of a viscous mass remains, which is mixed with 31 ml of acetone. The pH of the mixture is adjusted to pH 8 with concentrated hydrochloric acid and the product is crystallized by cooling. After cooling to -10 ° C, the mixture is filtered. The product is washed with 50% aqueous acetone and dried in a desiccator. 21.7 g of 7 - isopropoxy - 8 - (methyl - | 3 -oxyethylaminomethyl) - isoflavone are obtained, which melt at 80-81 ° C.

Salts of 7 - isopropoxy - 8 - (methyl - / 3 -oxyethylaminomethyl) - isoflavone.

7 - Isopropoxy - 8 - (avenging - - hydroxyethylaminomethyl) - isoflavone hydrochloride - monohydrate 10.0 g 7 - isopyropoxy 8 - chloromethyl isoflavoya react in Example 5, with 8 ml (3-methylaminoethanol in 50 ml of absolute ethanol. the mass (15 g) is dissolved in hot form in 100 ml of 1N hydrochloric acid and the product is salted out with the addition of 12.0 g of sodium chloride. On cooling, crystals are precipitated, which are filtered, dried and recrystallized from two times the amount of methanol. g salt that melts at 164-166 ° C. 7 - zopropoxy - 8 - (methyl -) 3 - hydroxyethylaminomethyl) - isoflavone nicotinate 30.0 g 7 - Isopropoxy - 8 (methyl - (3 - hydroxyethylaminomethyl) - isoflavone in a warm form, the solution is in 90 ml of isopropanol. A suspension of 10.2 is added to the solution. g of nicotinic acid in 32 ml of isopropanol. The mixture is boiled for 15 minutes and then cooled with stirring. The crystallized salt is filtered at -10 ° C and dried in a vacuum desiccator. 26.0 g of product are obtained, melting at 120- 121 ° C. 7 - Isopropoxy - 8 - (methyl - | 3 - hydroxyethylaminomethyl) - isoflavonbitartrate - hydrate. 10.0 g 7 - Isopropoxy -. 8 - (methyl - (3 -oxyethylaminomethyl) - isoflavone is dissolved in 40 ml of isopropanol in hot form. A suspension of 4.1 g of tartaric acid is added to the solution, in 10 ml of isopropanol. The mixture is boiled for 15 minutes. Crystallization begins already in a boiling solution. After cooling, the product is filtered off, washed with isopropanol, and then dried. 12.6 g of salt are obtained, which melt at 134-136 ° C. Example 7. To 10.0 g of 7-isopropoxy-8-piperidinomethyl isoflavone are poured 50 ml of absolute alcohol and 10 ml of piperidine. The mixture is boiled for 6 hours with refluxing. rotting with activated carbon, the mixture is filtered at -10 ° C and the base is crystallized out from the filtrate by intensive cooling. The product is washed with absolute ethanol and then dried at 60 ° C. 9.06 g of crystalline 7-isopropoxy-8-pmperidinomethyl isoflavone are obtained, which melt at 138 ° P. 7 - Isopropoxy-8-piperidinomethylisoflavonicnicotinate 3.8 g of 7-isopropoxy-8-piperieneinomethylisoflavone at boiling is dissolved in 15 ml of isopropanol. With stirring, 1.3 nicotinic acid suspended in SMH §5% f-f isopropanol is added to the solution. The mixture is boiled for 30 minutes and then cooled. The resulting crystals are filtered, rinsed with 85% isopropanol and dried in a desiccator. A salt containing 1 mol of crystallization is obtained, the yield is 4.4 g. The salt melts at 133-134 ° C. PRI me R 8. 10.0 g of 7 - isopropoxy - 8-. Chloromethyl isoflavone is mixed with 50 ml of absolute concentration and 6 ml of o: - n - butylamino - o: picoline. The mixture was boiled for two hours with refluxing. It is then clarified with activated carbon, filtered and the filtrate is evaporated to dryness in vacuo. 16.7 g of a viscous mass remains, which is dissolved in 33 ml of acetone. The solution is brought to a strongly acidic reaction with Kosher-Hydrogenic hydrochloric acid and the product is precipitated by adding water. After intensive cooling it is filtered, the precipitate is rinsed with water with acetone and dried in a water desiccator. 8.6 g of 7 - isopropoxy - 8 n - butyl - 2 (a - picolyl) - aminomethyl - isoflavone hydrochloride are obtained, which, after recrystallization from methanol, melts at 108-110 ° C. PRI me R 9. 10.0 g of 7 - isopropoxy - 8 chlorometalizedoflavone is suspended in 50 ml of absolute ethanol. 5 ml of pyrrho; shdina are added to the suspension and boiled with reflux for three hours. Already at 50 ° C, the substance begins to dissolve. The orange colored solution is clarified with activated carbon and then filtered and heated again in 100 ml of water. The mixture is processed as in Example 5. 10.5 g of 7-isopropoxy-8-pyrrolidinomethyl isoflavone are obtained, which melts at 115-116 ° C. Salts of 7-isopropoxy-8-pyrrolidinomethylisoflavone. 7 - Isopropoxy - 8 - pyrrolidinomethyl isoflavone hydrochloride hydrate 10.0 g of 7 - isopropoxy - 8 - hydroxydroxymethyl isoflavone are dissolved in heat in 38 ml of absolute ethanol. To the solution is added a mixture of 2.5 ml of concentrated hydrochloric acid (specific weight of 1.19) and 10 ml of absolute ethanol, then boiled for 15 minutes. The crystals which formed on cooling were isolated in Example 5. 10.25 g of hydrochloride hydrate were obtained. The product melts at 218-220 ° C. 7 - Isopropoxy - 8 - pyrrolidinomethylisoflavonicnicotinate 10.0 g of 7 - isopropoxy - 8 - pyrrolidinomethylisoflavone is dissolved in 30 ml of anhydrous isopropanol. A suspension of 3.4 g of nicotinic acid in 10 ml of anhydrous isopropanol is added to the solution and the mixture is boiled for 15 minutes. It is then treated as in Example 5. 12.60 g of nicotinate is obtained, which melts at 156-15 8 ° C. 7 - Isopropoxy - 8 - pyrrolidinomethyl isof lavone hebitartrate drat 10.0 g 7 - isopropoxy - 8 - pyrrolidinomethyl isoflavone at boiling is dissolved in 40 ml of isopropanol. The boiling solution is stirred with a suspension of 4.0 g of tartaric acid in 10 ml of anhydrous isopropanol, and the crystallization process begins. After boiling for 30 minutes, the mixture is cooled, filtered and washed. The separated crystalline product with cold 85% isopropanol. It is dried at atmospheric pressure.