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Structure of 115787-50-3 * Storage: {[proInfo.prStorage]}
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Stage #1: With aluminum (III) chloride In dichloromethane at 10 - 30℃; for 1 h; Stage #2: at 30 - 40℃; for 12 - 15 h; Stage #3: With water In dichloromethane at 0 - 5℃;
To a suspension of aluminium chloride (4 m/m) in dichloromethane (10 volumes), was added slowly bromoacetyl bromide (1.2 m/m) at 100C and then the temperature was brought to 300C. The reaction mass was stirred at this temperature for an hour and to this was added a solution of 2-hydroxybenzaldehyde (1) in dichloromethane at 300C. The reaction mixture was stirred at 35-400C for 12-15 hours and then quenched in water at 0-50C. The dichloromethane layer was separated and distilled off. To the slurry obtained, roe-heptane was added and stirred for 15 minutes. This slurry was then filtered and the wet cake was washed with n- heptane (2 volumes).The wet cake was dried at 500C to constant weight to obtain intermediate (2a).Yield: 55percent w/wHPLC purity: 97-99percent
Reference：
[1] Angewandte Chemie - International Edition, 2016, vol. 55, # 13, p. 4194 - 4198[2] Angew. Chem., 2016, vol. 128, # 13, p. 4266 - 4270,5
[3] Tetrahedron Asymmetry, 2008, vol. 19, # 15, p. 1824 - 1828
[4] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 5, p. 1548 - 1552
[5] Chemical Communications, 2018, vol. 54, # 25, p. 3106 - 3109
[6] Patent: WO2007/45857, 2007, A1, . Location in patent: Page/Page column 23; Figure 2
[7] Synthesis, 1988, # 12, p. 966 - 972
[8] Chemical Communications, 2017, vol. 54, # 2, p. 168 - 171
2
[ 22118-09-8 ]
[ 90-02-8 ]
[ 115787-50-3 ]
Yield
Reaction Conditions
Operation in experiment
84%
Stage #1: With aluminum (III) chloride In dichloromethane at 50℃; for 0.5 h; Stage #2: at 40℃; for 12 h;
Anhydrous aluminum trichloride (20 g, 0.15 mol) was added to a 250 mL three-necked flask, and 15 mL of methylene chloride was added dropwise with stirring. The temperature was raised to 50 ° C, 10 mL of a methylene chloride solution of 7 g (0.045 mol) of bromoacetyl chloride was added dropwise and the mixture was stirred for 30 minutes. Salicylaldehyde (3.66 g, 0.03 mol) was dissolved in 10 mL of dichloromethane, dropped into the reaction mixture at 40 ° C. and refluxed for 12 hours. The reaction mixture was slowly poured into 120 g of crushed ice with stirring, the pH was adjusted to 4, and the mixture was stirred for 30 minutes. Then dichloromethane was added. The organic layer was separated and the aqueous layer was washed with dichloromethane (30 mL x 3). The organic phases were combined and the organic phase was washed with distilled water and brine successively, then dried over anhydrous magnesium sulfate, filtered, concentrated and dried in vacuo to give a purple oil. After stirring with 15 mL of dichloromethane, 60 mL of petroleum ether was added at 0 ° C to precipitate a light brown solid which was filtered and dried to give 6.1 g of 5-(bromoacetyl)salicylaldehyde in a yield of 84percent.
80%
With aluminum (III) chloride In 1,2-dichloro-ethane at 70 - 80℃; for 36 h;
(1) 250mL three-necked flask was added anhydrous aluminum chloride 200g (0.15mol)150 mL dichloroethane,The temperature was raised to 70 ° C,150 mL of a solution of 66.1 g (0.042 mol) of bromoacetyl chloride in dichloroethane was added dropwise,To be dissolved completely,Into the reaction liquid, 150 mL of dichloroethane of 36.6 g (0.03 mol) of salicylaldehyde was dropped at 70 ° C,After the dropwise addition, the temperature was raised to 80 ° C and reacted for 36 hours.The reaction solution was slowly poured into 1.0kg crushed ice with stirring,Add 100mL concentrated hydrochloric acid, the organic layer was separated,The aqueous layer was extracted with 200 mL of dichloroethane, the combined dichloroethane layers,Washed with water (300 mL × 2), washed with saturated brine (300 mL), dried over anhydrous sodium sulfate,Concentrated to give a yellow oil,Crystallization from petroleum ether-methylene chloride, filtration,Dried to give a white solid Intermediate III58g, yield 80percent;
To a suspension of aluminium chloride (4 m/m) in dichloromethane (10 volumes), was added slowly bromoacetyl bromide (1.2 m/m) at 100C and then the temperature was brought to 300C. The reaction mass was stirred at this temperature for an hour and to this was added a solution of 2-hydroxybenzaldehyde (1) in dichloromethane at 300C. The reaction mixture was stirred at 35-400C for 12-15 hours and then quenched in water at 0-50C. The dichloromethane layer was separated and distilled off. To the slurry obtained, r°-heptane was added and stirred for 15 minutes. This slurry was then filtered and the wet cake was washed with n- heptane (2 volumes).The wet cake was dried at 500C to constant weight to obtain intermediate (2a).Yield: 55% w/wHPLC purity: 97-99%
Preparation (c) <strong>[115787-50-3]5-(Bromoacetyl)-2-hydroxybenzaldehyde</strong> (109g) is suspended in 2-propanol (920ml) and cooled to -3 C. with stirring. The reaction mixture is treated with 1,1dimethylethanamine (29.24g) and stirred at -3 C. to 0 C. for 30 minutes whereupon precipitation occurs. The reaction mixture is allowed to warm to room temperature, stirred for 90 minutes then cooled to 10 C. and filtered. The solid obtained is washed with ice cold 2-propanol (2*100ml) and dried in vacuo at 55 C for 18 hours providing 89g of 2-bromo-1-[3-[[(1,1-dimethylethyl)imino]methyl]-4-hydroxyphenyl]ethanone. NMR ((CDCl3:(CD3)2 SO): delta1.43 (9H,s),
Preparation (a) Aluminum trichloride (333g) is suspended in dichloromethane (350 ml) with stirring and heated to reflux temperature. To this slurry is added bromoacetyl chloride (99g) in dichloromethane (75ml) and after 30 minutes 2-hydroxybenzaldehyde (61.1 g) in dichloromethane (75ml) is added dropwise. The reaction mixture is refluxed for 16 hours and then cautiously poured onto ice (3kg), deionized water (300ml) and dichloromethane (500ml) with stirring Once the addition is complete the mixture is stirred for a further 15 minutes and the pH of the aqueous phase adjusted to pH 1-2 (pH paper) with concentrated hydrochloric acid if necessary. The organic layer is separated and the aqueous extracted with dichloromethane (3*250ml). The organic portions are combined, washed with deionized water (2*250ml) and saturated sodium chloride solution (500ml). The dichloromethane solution is dried over anhydrous magnesium sulfate and the dried solution evaporated under reduced pressure to give an oily solid (107g). The solid is slurried with a mixture of dichloromethane (20ml) and diethylether (180ml) and filtered The solid obtained is dried in vacuo at 50 to give 83g of a mixture (6:1) of the title compound and 5-(chloroacetyl)-2-hydroxybenzaldehyde. NMR (CDCl3): delta4.35 (s, CH2 -Br),
Add <strong>[115787-50-3]5-bromoacetyl-2-hydroxybenzaldehyde</strong> (200g) to a 5L three-necked flask, add propionic acid (500mL), tetrahydrofuran (1.5L), start stirring, cool down to 5-10 C, within a half hour, a small amount Add sodium borohydride (21.8g) in portions, add in the liquid phase, control the raw material, less than 1% of the raw materials, add 1L of water to the reaction system, stir at 0-5 C for 1 hour, filter, wash with 500 mL of water, and dry. The white solid was obtained in 190 g, the yield was 94%, the purity was 97.3%, and the over-reduced product was 1.9%.
88%
With sodium tetrahydroborate; acetic acid; at 0 - 20℃;Inert atmosphere;
Dissolve 12 g of 5- (bromoacetyl) salicylaldehyde in 50 mL of acetic acid, then cool to 0 C and add 2.3 g of sodium borohydride under nitrogen. After adding slowly warming to room temperature, stirring was continued until the reaction was complete. The pH of the reaction solution was adjusted to neutrality at 0 C with saturated aqueous sodium carbonate solution, then 100 mL of distilled water was added and the mixture was back-extracted three times with ethyl acetate. The organic phases were combined, the organic phase was washed with distilled water and brine, dried over anhydrous sodium sulfate, filtered, concentrated and dried in vacuo to give the crude product as a red oil. The crude product was purified by column chromatography (n-pentane:ethyl acetate 9: 1-2: 8) to give 10.6 g of 2-bromo-1-(4-hydroxy-3-(hydroxymethyl)phenyl)ethanone as pale yellow solid with a yield of 88%.
Compound 23 (1 equiv) can be dissolved under nitrogen in anhydrous THF, cooled in an ice-bath and then 95% NaH (l. l. equiv) can be added in small portions with vigorous stirring. After 15 minutes the THF solution of bromo-compound 22 (1 equiv) can be added dropwise with such a rate so that temperature is maintained below 5C. Then, the mixture is allowed to slowly warm up to room temperature with stirring overnight. The next day the reaction can be quenched by addition of 10% citric acid and diluted with ethyl acetate. After phase separation organic layer can be washed with sat. sodium bicarbonate, brine and dried over anhydrous magnesium sulfate. The crude material obtained after decantation and evaporation can be purified on silica gel.
cis-2-(3-(benzyl(2-(2,2-dimethyl-4H-benzo[d][1,3]dioxin-6-yl)-2-oxoethyl)amino)propyl)-4-(3,4-dimethoxyphenyl)-4a,5,6,7,8,8a-hexahydrophthalazin-1(2H)-one[ No CAS ]
2-(4-(benzyl(2-(2,2-dimethyl-4H-benzo[d][1,3]dioxin-6-yl)-2-oxoethyl)amino)butyl)-4-(3,4-dimethoxyphenyl)-4a,5,6,7,8,8a-hexahydrophthalazin-1(2H)-one[ No CAS ]
2-(5-(benzyl(2-(2,2-dimethyl-4H-benzo[d][1,3]dioxin-6-yl)-2-oxoethyl)amino)pentyl)-4-(3,4-dimethoxyphenyl)-4a,5,6,7,8,8a-hexahydrophthalazin-1(2H)-one[ No CAS ]
2-(6-(benzyl(2-(2,2-dimethyl-4H-benzo[d][1,3]dioxin-6-yl)-2-oxoethyl)amino)hexyl)-4-(3,4-dimethoxyphenyl)-4a,5,6,7,8,8a-hexahydrophthalazin-1(2H)-one[ No CAS ]
(2) 24.3 g (0.01 mol) Intermediate III was suspended in 100 mL isopropanol, and 31.5 mL(0.03mol) tert-butylamine, the reaction was stirred at 80 C for 2 hours, was slowly added a mixed solution of 25mL of concentrated hydrochloric acid and 25mL isopropanol,The reaction was stirred at room temperature for 16 hours. Filtered, washed with a little cold isopropanol, dried to give a light yellow solid Intermediate V20g, yield 73%;
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