SU656500A3 - Method of obtaining derivatives of chalcone - Google Patents

Description

This invention relates to the preparation of novel chalcone derivatives with pharmacological activity.

Some chalcone derivatives are known to have pharmacological activity against gastric ulcers.

Thus, 2,2,4, 4-tetraoxy-6-methoxy-3- (5-methyl-2-isopropenylhex-4-enyl) -halcon is known.

However, this compound is obtained by extraction from vegetable raw materials with low yield and low purity according to a complex procedure.

The aim of the invention is to obtain novel chalcone derivatives having a higher activity against gastric ulcers, along with low toxicity, npocTfcavi, and an industrial-friendly method based on the known condensation reaction of substituted acetophenone with substituted benzaldehyde under alkaline or acidic conditions.

The method of obtaining new chalcone derivatives of the general formula

g. / GK, KI

where R is - 4 hydrogen, hydroxy, lower alkyl, alkoxy, acyloxy; Z - 2 „- group of general formula

SKZ-0-G SNg-Sn C-SigD5 31

where n 1 or 2, or a group of the formula

-bNg- (1N YN YNZ

is that the compound of the general formula

Sosn,

W)

where RJ 2 is as defined above, it is condensed with a compound of the general formula

IL

THEY

30 where R, R 2, and Z are, as outlined above, in an organic solvent medium in the presence of alkali or mineral acid gfy O-SOO C. Co) dens11, iy can be performed by adding an alkali, such as sodium hydroxide and potassium hydroxide, or acids, such as hydrochloric and sulfuric acid, to a solution or suspension of substances in an organic solvent, such as methanol, ethanol and ethyl acetate, and stirring the resulting mixture for a few hours or several days. are cleaned of uterine fluid and cleaned, ec and neobhodimor by distillation, recrystallization or chromatography claim. The resulting compounds have activity against various types of gastric ulcers, namely acetic acid ulcer, similar to chronic gastric ulcer, stress ulcers of the ulcer caused by drug administration, for example aspirin, steroids, and other anti-inflammatory and antipyretic drugs. Target compounds excellently prevent and cure various types of experimental stomach ulcers in rats: the treatment of chronic stomach ulcers (acetic acid when injected with acetic acid) is accelerated, the development of ulcers and erosions (the name Shee during ligation of the pylorus, stress stress when squeezed or lowered animals Water, aspirin's name is delayed with the administration of aspirin. When the patented compounds are administered, no undesirable side effects are observed on the central and vegetative nervous systems. The toxicity of the present compounds is extremely low and with the administration of 5 g / kg Oral or 2 g / kg intravr to the tire and rats there are no deaths for 96 hours, with which the compounds can be administered without fear for a long time, without any side effect. Example 1. To a suspension of 218 mg of 4 (3-methyl-2 butenyloxyg) -ac tofenone and 200 mg of 4 (3-methyl-2-butenyloxy) -benzaldehyde in 8 ml of ethanol, add 3 ml of a 50% aqueous solution. Potassium hydroxide is stirred for 1 hour at room temperature, acidified with dilute hydrochloric acid, the solvent is evaporated, the residue is extracted with 3 x 30 hp ether, the extract is taken up in water and dried with aqueous sodium sulfate. After evaporation of the ether, the residue is distilled under a vacuum and 333 mg of 4.4-6is- (3-methyl-2-butenyloxy) -hapycone are obtained, t, bale, 99-102 ° C / 0.08 grams; mp, 95 Calculated,%: C, 79.75 g, And 7.50, C. f, C. Found;%: C, 79.77; H 7.48. 4 Example 2. To a solution of 3 g of salicylic aldehyde in 20 mp of acetone, add 4.1 g of potassium carbonate and 4.9 g of 3-methyl-2-butenyl bromide, stir for 2 hours at room temperature and obtain 3.5 g of 2 - (3-methyl-2 butenyloxy) -benzaldehyde. To a solution of 3.3 g of p- (3-methyl-2-butenyloxy) acetophenone and 3.0 g of the resulting 2- {3-methyl-2-butenyloxy) -benzaldehyde in 5 ml of ethanol are added 30 ml of 50% OH. potassium hydroxide solution, stirred for 3 hours at room temperature, 200 ml of water are added, acidified with hydrochloric acid and extracted with ether. The extract is distilled under vacuum and 3.6 g of 2, 4-bis- (3-methyl-2-butenyloxy) -chalcone are isolated, b.p. lOB-llO C / / O, 1 mm; m.p. , Calculated,%: C 79.75; H 7.50. About 3. R,%: C 79.35; H 7.49. Example 3. To a solution of 3.3 g of p- (3-methyl-2-butenyloxy) acetophenone and 3.0 g of m- (3-methyl-2-butenyloxy) benzaldehyde in 5 ml of ethanol was added 30 ml of 50% a solution of potassium hydroxide and stirred for 3 h at room temperature. After water was added, the reaction mixture was acidified with hydrochloric acid and extracted with ether. The extract was distilled under vacuum. 3.1 g of 3,4-bis- (3-meth L-2-butenyloxy) chalcone, t. Bale, 111-11 C / 0.1 mm were obtained. Example 4. To a suspension of 260 mg of 2-OXI-4- (3-methyl-2-butenyl) -acetophenone and 219 mg of 4- (3-methyl 2 6 -utenkoxy) -benzaldehyde 3 with 8 ml of ethanol was added 3 ml of a 50% solution potassium hydroxide and stirred for 1 h at room temperature. The reaction mixture is acidified with hydrochloric acid, the solvent is evaporated, the residue is extracted with 3x30 ml of ether, the extract is washed with water and dried with anhydrous sodium sulfate. After evaporation of the ether, the residue is distilled under vacuum and 390 mg of 2-ca. bis (3-methyl-2-butenyloxy) chalcone, bp, 109-114C / 0.1 mm; m.p. 87-88.5 ° C. Calculated,%; C 76.50; H 7.19. Co-Nd O Found; %: C, 76.94; H 7.12, Example 5. To a solution of 130 mg of 2-methoxy-4- (3-methyl-2-butenyloxy) acetophenone and G20 mg of p- (3-methyl-2 butenyloxy) -benzaldehyde in 2 ml of ethanol are added 3 ml of 50% potassium hydroxide solution and c-stir for 1 h at room temperature. The reaction mixture is acidified with dilute hydrochloric acid, the solvent is evaporated, the residue is extracted with ether, the extract is washed with water and dried over anhydrous sodium sulfate. After removal of the ester, the residue was distilled under vacuum and 130 mg of 2-methoxy-4, (3-methyl-2-butenyloxy) chalcone, g, kip was taken out. 117-119 С / О, 09 mm. Example 6. To a solution of 418 m of 4-hydroxy-3- (3-methyl-2.-butenyl) -acetophenone and 390 mg of 4- (3-methyl-2-butenyloxy) -benzaldehyde in 2 ml of ethanol are added 20 ml of 50% potassium hydroxide solution, stirred for 3 hours at room temperature, add water, acidify to pH 2 with dilute hydrochloric acid and extract with ether. The solvent is evaporated, the residue is passed through a column of silica gel, eluting with acetone-hexane, to obtain 310 m of a colorless powder of 4-hydroxy-3- (3-methyl-2-butenyl) -4- (3-methyl-2-butenyl oxy, ) -halkona, so pl. 145-147 C. Example 7. To a suspension of 440 mg of 2,4-dioxy-3- (3-methyl-2 buteyl) acetophenone and 380 mg of p- (3-methyl-2-butenyloxy) benzaldehyde in 2 ml of ethanol was added 8 ml of a 40% potassium hydroxide solution, stirred for 72 hours at room temperature, water was added, acidified to pH 2 with dilute hydrochloric acid, and extracted with ether. The solvent is evaporated and the residue is passed through a column of silica gel, eluting with benzene, and 95 mg of yellow needles of 24-dioxy 3- (3-methyl-2-butenyl) -4- {3-methyl-2-butenyloxy) are obtained 167-168,. -halkona, etc .: C 76.50; H 7.19. Calculated% Found,%: C 76.53; H 7.17. Example 8. To a suspension of 660 mg of 2,4-DIOXI-5- (3-methyl-2-buteyl) acetophenone and 571 mg of p- (3-methyl-2-butenyloxy) -benzaldehyde in 3 ml of ethanol are added 12 ml of 40% potassium hydroxide solution, stirred for 1 h at 6 OC, proceed further as in example 7, and get 280 mg of orange needles of 24-dioxy-5- {3-methyl-2-butenyl) (3-methyl -2-butenyloxy) -halcone, so pl. 145-146 ° C. Example 9. A solution of 9.9 g of 2,4-diacetoxy 3- (3-methyl-2-butenyl-acetophenone and 9.6 g of 2-methyl-4- (3-methyl-2-butenyloxy) -benzaldehyde with 160 ml of anhydrous ethyl acetate is saturated hydrogen chloride at 0 ° C and stir at room temperature for 12 hours. Then dissolve the solution by evaporation in a water bath. After cooling, the residue is dissolved in ether and the ether solution is washed with water and dried with anhydrous sodium sulfate, and the ether is evaporated. silica gel column and elute with acetone-hexane to give 2.1 g of 2, 4-diacetoxy-2-methyl-3- (3-methyl-2-butene 1 ) -4- (W-mepgd-3-buteni oxn) -halcon, bp 13013C / o, in mm. Example 10, to a solution of 3.1 g of 2-hydroxy-- (W-methyl-2-butenyloxy ) acetophenone and 3.2 g of 4-methoxy-3 (3-methyl-2-butenyl) -benzaldehyde in 6 ml of ethanol are added with 30 ml of 50% potassium hydroxide solution and stirred for 3 hours at room temperature / acidified with diluted hydrochloric acid, the solvent is evaporated, the residue is extracted with ether, the extract is washed with water and dried with anhydrous sodium sulfate. After removing the ether, the residue is recrystallized from methanol-acetone to obtain 4.7 g of yellow needles. 2-hydroxy-4-methoxy-3- {3-methyl-2-butenyl) -4- (3-methyl-2-butenyloxy) ) -halkona, mp, 9192 0. Example 11. To a solution of 3.2 g of 2-methoxy-4- (3-methyl-2-butenyloxy) acetophenone and 3.4 g of 2-hydroxy 4-methoxy-3- (3-methyl-2-butenyl) - 30 ml of 50% potassium hydroxide solution is added to benzaldehyde in 6 ml of ethanol and stirred for 3 hours at room temperature, acidified with dilute hydrochloric acid, the solvent is evaporated, the residue is extracted with ether, the extract is washed with water and dried with anhydrous sodium sulfate. After removal of the ester, the residue is distilled under vacuum to obtain 4.5 g of 2-hydroxy-2, 4-dimethoxy-3- (3-methyl-2-butenyl) -4- (3-methyl-2-butenyloxy) chalcone, th.kip, 131-133 ° С / 0.09 mm. Example 12. to a solution of 7.6 g of 2,6-dimethoxy-4- (3-methyl-2-butenyloxy) acetophenone and 7.0 g of 4-acetoxy-3- (3-methyl-2 butenyl) -benzaldehyde in l40 ml of anhydrous ethyl acetate was added 40 ml of a 40% solution of sulfuric acid and stirred for 6 hours at 0 ° C. The solvent is evaporated, water is added to the residue and it is extracted with ether. The extract is washed with water, dried with anhydrous sodium sulfate, the ether is evaporated, the residue is distilled under vacuum to obtain 1.9 g of 4-acetoxy -2,6-dimethoxy-3- (3-methyl-2-butenyl) -4- (3- methyl-2-butenyloxy) -halcone, so kip. 129-131 ° C / O, 09 mm. H 7.16, Calculated,%: C 72.78; Found,%: C 72.31; H 7.22, Example 13, To a solution of 2.7 g of p- (3,7-dimethyl-2,6-octadienyloxy) acetophenone and 2.6 g of p- (3,7-dimethyl-2, b-oxtadienyloxy } -benzaldehyde in 10 ml of ethanol was added 30 1ll of 50% sodium hydroxide solution and stirred for 1 hour at

SO C. After the addition of the holohchgop water, the reaction; On the basis of a mixture of hydroxy acid and hydrochloric acid and extraheroeshth efI rum, the extract is distilled under a vacuum and 3.2 g of 4, 4-bis- (3, 7 1: 1 non-hydroxy-2, G-oxadienyloxn) are obtained. Khalkona, T..KIP. Ы4. -116 ° С / 0.06 nl m.p. 6970 ° C

Calculated% C 8.1.9 9 j And.

 h

Found,% s C 81,89; H 8.70,

Example 14, K rasBBOr5 3 g 2, 4 Dkmethoxy 3- {3-netl 2 ™ 6utenyl) -acetophenone and 3.5 g 4-methoxy-2 - (3, 7 dimethyl-2, b-octadienyloxy) - - 40 ml of a 50% potassium hydroxide solution are added to 10 ml of methanol in benzaldehyde; the mixture is stirred at room temperature for 3 hours; after addition of water, the extras are acidified with hydrochloric acid and extracted with ether. Exgracate is distilled under vacuum to obtain 3.7 g of 24 f 4 trimethoxy -3- {3-methyl 2 butenyl), 7 Dimethyl-2, b octadiyoyloxy) Calcone, bp. 122-125 ° C / 0.08 MVJ,

Calculated,%: C, 76.41; H, 8.16.

Found,% s C 76.49 H 8.11.

Particularly useful are the compounds obtained in Examples 1-14 as well.

 f 4 bis-- (3-methyl-2-butenyloxy) -halkon,. 1JO - 112 C /. / OD mm

4 Oxy-3- {3-netil-2 butenyl) -4 (3 Methyl-2-butenyloxy) -halkon, tkkp 5.30-132 C / O, O2 No. t; m.p. 139 ™ 140 ° C;

J 2 4-dioxy-3 (3-methyl-2-butenyl) -4- (3 ™ methyl 2-butoxyloxy) -halkon, t, kip from 14 5-14 7 ° С / О, 11 mm t, pl. 14 2 143 С |

3-methyl-4, 4-bis- (3, 7-dimethyl 2, b-octadnenyloxy) -halkon, t, kip, 119121 0/0, 11 Mivi, - /

4 Oxy 4 ™ methoxy 3 (3 methyl-2-butenyl) -2 (3,. Methyl-2, 6 octadienyloxy) -halkonf, kip. 133-135 ° (: / 0,09 mm ;,

4 - OXI-2, 4 dimethoxy 3 {3 methyl 2 butenyl) -2- {3.7 dimethyl-2,6 kctadienyloxy) -halcon, t, kip, 131 mm.

Claims (1)

Invention Formula The process for the preparation of chalone derivatives of the general formula where R 2 R 2 each independently of one another denotes hydrogen, noxy group, lower alkyl, alkoxy, acyloxy groups; Z is a group of the general formula S11z -O-GYL.2- (Lf7 N i g where n is 1 or 2, or a group of the formula - H2-C№i; - (; jij (III}, characterized in that. compound of general formula Zg shyoyn. Cs where r r and z The values indicated above are condensed with a compound of the general formula THEY where R Z as above, in the environment of an organic solvent in the presence of alkali or mineral. Acid at 0-100 0 Priority featured: 30. with Z in the ortho-position. 19,01,74 when in meta position. Sources of information taken into account in the examination 1, Japan Patent No. 691783, cl. ZOA / 31, 1972,