5-Bromo-4-chloro-2-thiophenecarboxylic acid

To a solution of -(5-bromo-4-chloro-2-thienyl)ethanone (3.4 g, 14.3 mmol) in 1 N NaOH (200 mL) at 0 C was added BrInto a 10-mL round-bottom flask was placed 4-chlorothiophene-2-carboxylic acid (5 g, 30.75 mmol, 1.00 equiv), NBS (10 g, 101.69 mmol, 1.80 equiv), and N, N- dimethylformamide (10 ml). The resulting solution was stirred for 12 h at 50 C in an oil bath. The resulting mixture was poured into water and extracted by ethyl acetate (3x50 ml), the organic layer was concentrated under vacuum. The residue was applied onto a silica gel column (mobile phase: ethyl acetate/petroleum ether (1 : 1)), and 6 g (81% yield) of 5- bromo-4-chlorothiophene-2-carboxylic acid. LCMS (ESI): RT = 0.49 min, m/z = 241 [M+l]+; 1H NMR (300 MHz, DMSO- d6 , rrth) d 13.8 (br, 1H), 7.71 (s, 1H).Into a 20-mL round-bottom flask was placed 5-bromo-4-chlorothiophene-2- carboxylic acid (1 g, 4.14 mmol, 1.00 equiv), Zn(CN)2 (2.5 g, 20.6 mmol, 5.00 equiv), N, N- dimethylformamide (5 mL), and Pd(PPh3)4 (1.25 g, l.03mmol, 0.25 equiv). The resulting solution was stirred for 2 h at 80 C in an oil bath. The reaction progress was monitored by LCMS. The resulting mixture was poured into water and extract by ethyl acetate (3x20 ml). The organic layer was concentrated under vacuum to give crude product. The residue was applied onto a silica gel column (mobile phase: ethyl acetate/petroleum ether (1 : 1)) to give 0.6 g (77% yield) of 4-chloro-5-cyanothiophene-2-carboxylic acid as a white solid. LCMS (ESI): RT = 0.87min, m/z = 188[M+1]+To a solution of compound BB-4-4 (40.00 g, 165.64 mmol, 1.00 eq) in methanol (300.00 mL) was addedconcentrated sulfuric acid (1.62 g, 16.56 mmol, 0.10 eq) dropwise while stirring. And then the reaction mixture washeated to 100C and reacted for 15h. The reaction mixture was concentrated under reduced pressure to remove solventsand the residue was added water (150mL). The mixture was stirred to disperse product and then filtered, the filter cakewas dried to give product BB-4 (38.00 g, 148.72 mmol, 89.78% yield) as khaki solid. 1H-NMR(400MHz, DMSO-d6) delta:7.84 (s, 1H), 3.89-3.81 (m, 3H).2.41 g (10 mmol) of compound II-3 and 0.85 g (10 mmol) of compound III were dissolved in 20 mL of dry THF.Stir at room temperature, 2.48 g (12 mmol) of N, N'-dicyclohexylcarbodiimide (DCC) and 0.1 g were added 4-dimethylaminopyridine(DMAP)After the addition, The reaction mixture was stirred at room temperature overnight.TLC tracking revealed that the reaction was complete.The reaction mixture was carefully poured into 200 mL of ice water.Stir, Extracted with 50 mL × 3 CH 2 Cl 2 , Combine the extracted phases, 100mL of 1% dilute hydrochloric acid andWash with 100mL 5% brine, Dry over anhydrous sodium sulfate.Filtering to remove the desiccant, The filtrate was evaporated to dryness on a rotary evaporator.The residue was purified using silica gel column chromatography.Compound IV-3 was obtained.2.42 g (10 mmol) of compound II-3 and 0.85 g (10 mmol) of compound III were dissolved in 20 mL of dry THF.Stir at room temperature, add 2.48 g (12 mmol) of N, N'-dicyclohexylcarbodiimide (DCC) and 0.1 g of 4-dimethylaminopyridine(DMAP), After the addition was completed, the reaction mixture was stirred at room temperature overnight and was observed by TLC.The reaction mixture was carefully poured into 200 mL of ice water, stirred, and extracted with 50 mL×3 CH 2 Cl 2 .The extract phases were combined and washed successively with 100 mL of 1% diluted hydrochloric acid and 100 mL of 5% brine and dried over anhydrous sodium sulfate.The desiccant was removed by suction filtration, and the filtrate was evaporated to dryness on a rotary evaporator.Compound IV-3 was obtained.2.41 (10 mmol) of compound II-1 and 0.57 g (10 mmol) of compound III were dissolved in 20 mL of dry THF, After stirring at room temperature, 2.48 g (12 mmol) of N, N'-dicyclohexylcarbodiimide (DCC) andAfter 0.1 g of 4-dimethylaminopyridine (DMAP) was added, the reaction mixture was stirred at room temperature overnight.TLC tracking found that the reaction was complete. The reaction mixture was carefully poured into 200 mL of ice water and stirred.Extract with 50mL×3CH 2 Cl 2 , combine the extraction phases, and successively use 100mL 1% dilute hydrochloric acid and 100mLIt is washed with 5% brine and dried over anhydrous sodium sulfate. The desiccant is filtered off with suction and the filtrate is evaporated to dryness on a rotary evaporator.The residue is purified using silica gel column chromatography to give compound IV-3

Molecular Weight:241.49
XLogP3:3.1
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:1
Exact Mass:239.86474
Monoisotopic Mass:239.86474
Topological Polar Surface Area:65.5
Heavy Atom Count:10
Complexity:155
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes