2,5-Dibromobenzeneacetic acid

In a 500 ml four-neck reaction flask, 82 g of Intermediate 3 was added, and 400 ml of a 2N aqueous solution of sodium hydroxide was added and the mixture was heated to 100° C. and refluxed.TLC monitored the reaction, cooled to room temperature, added dropwise with 36percent hydrochloric acid to pH=8, and the aqueous layer was extracted with ethyl acetate.The aqueous layer was adjusted to pH=1 to 2 with 36percent hydrochloric acid, solids were precipitated, and filtered to obtain an off-white solid 2, 5-dibromophenylacetic acid, dried 73 g, yield 83percent.The 5-bromofluorenone 670.7 g obtained in the previous step, Add 1320ml of water and cool to -5-0 °C in an ice bath.Then add 1100g of hydrogen bromide (48percent) aqueous solution and stir.Most of the raw materials are dissolved, and the temperature is controlled within the range of -5-0 °C.Add 143 g of sodium nitrite to a solution of 286 ml of water.During the period, the control temperature does not exceed 0 °C, about 15 minutes, The incubation reaction was continued for 1 h, and a large amount of brown granular solid (diazonium salt) was precipitated in the reaction solution for use.In another 10000ml four-necked flask, 297g of cuprous bromide, 22g of copper bromide, 13200ml of water, hydrogen bromide(48percent) 1100g of aqueous solution, stirred, the reaction solution was dark red, heated to 20-25 ° C, the diazonium salt obtained in the previous step was added dropwise.After the completion of the dropwise addition, the reaction was continued for 1 h, the temperature was lowered to about 5 ° C, the temperature was kept for 0.5 h, and the filter cake was washed with cold water until the washing liquid was colorless. drying, The solid 2, 5-dibromophenylacetic acid 746 g was obtained in a yield of 80.5percent, and the HPLC purity was 98.8percent.300.0 g of bromoindolinone (Formula II) prepared in the previous step was put into a reaction flask, 600 ml of water was added, and the temperature was lowered to -5 to 0 ° C in an ice bath, Then 493.5g of hydrogen bromide (48percent) aqueous solution was added and stirred. Most of the raw materials were dissolved and the temperature was controlled at -5-0 ° C. A solution of 65.0g of sodium nitrite dissolved in 130ml of water was added dropwise, During the temperature does not exceed 0 , about 15min plus Bi, continue to heat the reaction 1h, The reaction liquid has a large number of brown granular solid precipitation, stand-by. In another reaction flask, 135.0 g of cuprous bromide, 10.0 g of cupric bromide, 600 ml of water and 500 g of a hydrogen bromide (48percent) aqueous solution were added and the mixture was stirred. The reaction mixture was dark red, The temperature was raised to 20-25 ° C., the diazonium salt obtained from the previous step was added dropwise and the reaction was continued for 1 h after the completion of the incubation.Cool to about 5 , incubated 0.5h, filtered, the filter cake washed with cold water to wash colorless.Drying afforded 322.5g of solid, HPLC purity 99.1percent.General procedure: For the synthesis of 10a-10h, the mixtures of 2-(3, 5-dibromo-4-methoxyphenyl)acetic acid(4, 80 mg, 0.25 mmol, 1 equiv.), hydroxybenzotriazole (HOBT) (19 mg, 0.125 mmol, 0.5 equiv.), EDCI(58 mg, 0.375 mmol, 1.5 equiv.), triethylamine (75 mg, 0.75 mmol, 3 equiv.), and corresponding amines9a-9h (0.25 mmol, 1 equiv.) in 5 mL of CH2Cl2 were stirred at room temperature overnight. For thesynthesis of 12a-12l, the mixtures of corresponding phenylacetic acids 11a-11l (0.26 mmol, 1 equiv.), HOBT (20 mg, 0.13 mmol, 0.5 equiv.), EDCI (60 mg, 0.39 mmol, 1.5 equiv.), triethylamine (79 mg, 0.78 mmol, 3 equiv.), and N1-(1, 2, 3, 4-tetrahydroacridin-9-yl)heptane-1, 7-diamine (80 mg, 0.26 mmol, 1 equiv.) in 5 mL of CH2Cl2 were stirred at room temperature overnight. The above solutions were evaporated, and the residues were purified by flash chromatography using CH2Cl2:MeOH = 10:1 asan eluent to give the target compounds 10a-10h and 12a-12l.The 5-bromofluorenone 670.7 g obtained in the previous step, Add 1320ml of water and cool to -5-0 C in an ice bath.Then add 1100g of hydrogen bromide (48%) aqueous solution and stir.Most of the raw materials are dissolved, and the temperature is controlled within the range of -5-0 C.Add 143 g of sodium nitrite to a solution of 286 ml of water.During the period, the control temperature does not exceed 0 C, about 15 minutes, The incubation reaction was continued for 1 h, and a large amount of brown granular solid (diazonium salt) was precipitated in the reaction solution for use.In another 10000ml four-necked flask, 297g of cuprous bromide, 22g of copper bromide, 13200ml of water, hydrogen bromide(48%) 1100g of aqueous solution, stirred, the reaction solution was dark red, heated to 20-25 C, the diazonium salt obtained in the previous step was added dropwise.After the completion of the dropwise addition, the reaction was continued for 1 h, the temperature was lowered to about 5 C, the temperature was kept for 0.5 h, and the filter cake was washed with cold water until the washing liquid was colorless. drying, The solid 300.0 g of bromoindolinone (Formula II) prepared in the previous step was put into a reaction flask, 600 ml of water was added, and the temperature was lowered to -5 to 0 C in an ice bath, Then 493.5g of hydrogen bromide (48%) aqueous solution was added and stirred. Most of the raw materials were dissolved and the temperature was controlled at -5-0 C. A solution of 65.0g of sodium nitrite dissolved in 130ml of water was added dropwise, During the temperature does not exceed 0 , about 15min plus Bi, continue to heat the reaction 1h, The reaction liquid has a large number of brown granular solid precipitation, stand-by. In another reaction flask, 135.0 g of cuprous bromide, 10.0 g of cupric bromide, 600 ml of water and 500 g of a hydrogen bromide (48%) aqueous solution were added and the mixture was stirred. The reaction mixture was dark red, The temperature was raised to 20-25 C., the diazonium salt obtained from the previous step was added dropwise and the reaction was continued for 1 h after the completion of the incubation.Cool to about 5 , incubated 0.5h, filtered, the filter cake washed with cold water to wash colorless.Drying afforded 322.5g of solid, HPLC purity 99.1%.

Molecular Weight:293.94
XLogP3:2.8
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:2
Exact Mass:293.87141
Monoisotopic Mass:291.87345
Topological Polar Surface Area:37.3
Heavy Atom Count:12
Complexity:172
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes