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With sodium hydroxide; sodium iodide; potassium carbonate In ethanol |
1.A (A)
(A) 5-(2-Formyl-3-methoxyphenoxy)pentanoic acid 2-Hydroxy-6-methoxybenzaldehyde (16.875 g., 0.111 M), ethyl 5-bromopentanoate (23.25 g., 17.6 ml., 0.111 M), anhydrous potassium carbonate (16.5 g.), sodium iodide (0.675 g.) and 95% ethanol (150 ml.) were refluxed with stirring (16 hrs). The cooled reaction mixture was filtered and the solid washed well with ethanol. The filtrate was evaporated to dryness and the residue partitioned between ether and water. The ethereal layer was separated and washed with 2 N sodium hydroxide solution, water, dried (sodium sulphate) and evaporated. The residue was dissolved in 95% ethanol (300 ml.) and 0.66 N sodium hydroxide solution (450 ml.) and stirred at ambient temperature (4 hrs). The reaction mixture was evaporated to half volume and diluted with water. The mixture was extracted once with ether and the aqueous layer acidified with concentrated hydrochloric acid with cooling. The crystalline solid formed was filtered off and washed well with water. Recrystallisation from ethyl acetate-petrol gave 5-(2-formyl-3-methoxyphenoxy)pentanoic acid, m.p. 99°-101° C. (Found: C, 61.98; H, 6.58. C13 H16 O5 requires C, 61.89; H, 6.39%). |
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Stage #1: 6-methoxysalicylaldehyde; ethyl 5-bromovalerate With potassium carbonate; sodium iodide In ethanol for 16h; Reflux;
Stage #2: With ethanol; sodium hydroxide at 20℃; for 4h; |
In Figure 1,2-hydroxy-6-methoxybenzaldehyde (16.875g, 0.111M),Ethyl 5-bromovalerate (23.25g, 17.6ml, 0.111M), anhydrous potassium carbonate (16.5g),Sodium iodide (0.675 g) and 95% ethanol (150 ml) were refluxed with stirring (16 hours).The cooled reaction mixture was filtered and the solid was washed with ethanol.The filtrate was evaporated to dryness and the residue was partitioned between ether and water.The aqueous solution was separated with 2N sodium hydroxide solution, dried (sodium sulfate) and evaporated.Dissolve the residue in 95% ethanol (300ml) and 0.66N sodium hydroxide solution (450ml),And stir at ambient temperature (4 hours). The reaction mixture was evaporated to half volume and diluted with water.The mixture was extracted once with ether, and the aqueous layer was acidified and cooled with concentrated hydrochloric acid.The filtered crystalline solid was filtered off and rinsed with water.Recrystallization from ethyl acetoacetate gives 5- (2-formyl-3-methoxyphenoxy) pentanoic acid,M.P. 99-101 ° C (found C, 61.98; H, 6.58). C13H1605 requires C, 61.89; H, 6.39%).5- (2-formyl-3-benzyloxyphenoxy)Valerate(3.61g, 0.01M),Potassium hydroxide (1.19g, 0.021m) and ethanol (40ml) were mixed and stirred at 50-60 ° C for 5 hours.Then the ethanol was removed in vacuo and the residue was dissolved in water (50 ml),The solution was extracted with ether (2 × 80 ml).Then add 2N aqueous hydrochloric acid and the product extracted with ether (3 × 50n1) to acidify the water layer,And the combined extract was washed with water until neutral, dried, and concentrated in vacuo,get5- (2-formyl-3-benzyloxyphenoxy) pentanoic acid,3g, 91% as A.Yellow oil crystallizes at room temperature. The crude solid is crystallized from benzene / petroleum at 30-40 ° C,Light cream crystals were obtained.A mixture of 2-hydroxy-6-benzyloxybenzylidene-HydE.(3g, 0.013m), ethyl 5-bromovalerate (2.75g, 0.013m),Anhydrous potassium carbonate (2.16g, 0.0156m),Sodium iodide (0.195g) and dry dimethylformamide (15ml) were stirred at 60-80 ° C for 3 hours,Then it was stirred overnight at room temperature.The mixture was then poured into water (50ml) and the product was extracted with ether (2x80ml),And washed with 10% aqueous sodium hydroxide solution (2 × 20ml), then neutralized with water and dried,Evaporate, get5- (2-formyl-3-benzyloxy-phenoxy) valeric acid ethyl ester (4g),86% is light yellow oil.Dissolve 5- (2-formyl-3-methoxyphenoxy) valeric acid (1) (25g, 0.099m) in dry methylene chloride (600ml) and stir at 70 ° C,Carbon trichloride (50g) was added in a dry dichloromethane (100ml) from an equal pressure dropping funnel.The reaction mixture did not rise above 60 ° C. The mixture was stirred at 70 ° C,Then soak in warm water to room temperature. After stirring at room temperature (1 hour),The mixture was carefully poured into a 10% sodium acetate solution (500ml).The resulting mixture was filtered and the layers were separated. The aqueous phase was extracted once with dichloromethane,The combined organic solution was evaporated. Dissolve the residue in ethyl acetate / ether (1: 1),Extract with 5% sodium bicarbonate solution (4 × 250 ml). Acidify with concentrated hydrochloric acid and extract with ethyl acetate.The combined extract was washed with water, dried (sodium sulfate) and evaporated.The residue was dissolved in acetone (100 ml), treated with swirling flow, and 40/60 gasoline (400 ml) was added.Decant the light yellow supernatant from the red tar residue and filter.Evaporation yields 5 (2-formyl-3-hydroxyphenoxy) pentanoic acid from benzene / gasoline,M.P. 96-98 ° C.To a stirred mixture of metallic magnesium (15.4g, 0.636m) and diethyl ether (50ml) was added 10ml of iodine (40.3g, 0.157m) in diethyl ether solution (sodium dry, 500ml).When the reaction starts, the remaining iodine solution is added dropwise at such a rate to cause gentle reflux.After the addition is complete, the reaction mixture is heated to reflux until a colorless solution is obtained.The cooled reaction mixture was filtered, and the unreacted magnesium metal was washed with diethyl ether (100 ml).The colorless solution of magnesium iodide thus obtained was added dropwise to ethyl-2- (2-formyl-3-methoxyphenoxy) valerate (30 g, 0.106) in tetrahydrofuran (5 molecular sieves, 300 ml) M) in the solution,Gentle reflux is performed at this rate. A small yellow precipitate dripped from the solution.The mixture was stirred at reflux for 5 hours.The cooled reaction mixture was poured into 10% hydrochloric acid (400 ml).The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 × 150 ml).The combined organic phase containing ethyl 5- (2-formyl-3-hydroxyphenoxy) valerate was washed with water (2 × 150 ml) and then extracted into 2N sodium hydroxide solution (3 × 150 ml).The combined water extract was acidified with concentrated hydrochloric acid and cooled on ice.The precipitate was filtered, washed with water, dried, and then quickly washed with a gasoline / ethanol mixture (6: 1, 60 ml) to remove some color.The crude product was dried in a phosphorus pentoxide dryer to obtain a dark peach solid,Then dissolved in ethyl acetate (250ml), added alumina (neutral, 10g) and charcoal (5g),The mixture was vigorously stirred for one hour, and then filtered to obtain a yellow solution.The solvent was removed in vacuo to obtain 5 (2-formyl-3-hydroxyphenoxy) pentanoic acid from ethyl acetate / petrol.Polysorbate 20, polyvinylpyrrolidone, sodium chloride and chlorocresol were dissolved in water and injected.Sterile filter, 0.22 ° C.The sterile compound is ground into particles below 20 μm and added to the filtered solution.Until uniform dispersion is achieved. Load into sterile glass bottles.In the aerated sample of homozygous sickle cell blood, it was maintained at 150 mm oxygen tension.Hg, the proportion of normal discoid red blood cells is usually greater than 90%.If the oxygen tension decreases, the proportion of normal cells decreases,Because the ratio of sickle and singular cell increases in the opposite direction, and the oxygen tension is 28 mm.The proportion of normal cells is 45-65%. In the presence of an effective concentration of resistance to Fusarium,The proportion of normal cells under this low oxygen tension increases. |
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