2-[2-(4-Chlorophenyl)acetyl]benzoic acid

Proportionion of p-chlorophenylacetic acid, phthalic anhydride and freshly melted sodium acetate in a reaction kettle, Rapidly heated to about 250 ° C, Stirring reaction at 240-250 ° C for 3 hours, the water produced during the reaction is discharged from the tail pipe;The reaction mixture is then placed in an open heat-resistant container while hot.Cool with stirring and add cold absolute ethanol.Heating to dissolve the solid as much as possible, cooling and filtering.Wash with absolute ethanol, filter, dry.The obtained solid is added to a solution of sodium hydroxide and water, stirred under reflux for 4 hours, cooled, diluted with water, acidified to pH 2-3 with 20percent hydrochloric acid, and stirred, cooled, and precipitated as a solid oil. , filtered, dried to obtain a crude product, the crude product was dissolved in acetone, the insoluble matter was filtered off, and acetone was evaporated.The residue was recrystallized from ethyl acetate.Get the product. MP 142-144 ° C, yield 80percent.Proportionion of p-chlorophenylacetic acid, phthalic anhydride and freshly melted sodium acetate in a reaction kettle, Rapidly heated to about 250 C, Stirring reaction at 240-250 C for 3 hours, the water produced during the reaction is discharged from the tail pipe;The reaction mixture is then placed in an open heat-resistant container while hot.Cool with stirring and add cold absolute ethanol.Heating to dissolve the solid as much as possible, cooling and filtering.Wash with absolute ethanol, filter, dry.The obtained solid is added to a solution of sodium hydroxide and water, stirred under reflux for 4 hours, cooled, diluted with water, acidified to pH 2-3 with 20% hydrochloric acid, and stirred, cooled, and precipitated as a solid oil. , filtered, dried to obtain a crude product, the crude product was dissolved in acetone, the insoluble matter was filtered off, and acetone was evaporated.The residue was recrystallized from ethyl acetate.Get the product. MP 142-144 C, yield 80%.General procedure: To a solution of2-acetyl-benzoic acid (164 mg, 1.0 mmol) and TSTU (301 mg, 1.0 mmol) inCH2Cl2 (5.0 mL) was added DIEA (2.0 mmol). The reaction was allowed to stir atroom temperature for 6 h. Then, the reaction mixture was poured into water(10 mL), extracted using EtOAc (3 10 mL). The combined organic layers werewashed by brine with water (3 10 mL) and NaHCO3 aqueous (3 10 mL) anddried over Na2SO4. The solvent was removed by rotary evaporation to yield (Z)-3-ylidenephthalide 1a as a white solid (144 mg, 0.99 mmol, 99%)The aqueous solution of 1H-azepine, 4-hydrazinohexahydro-1-methyl dihydrochloride of the previous step, was cooled down to a temperature below 10 C and 420 g of sodium hydroxide 50% (3.35 eq) were added. 420 g of benzoic acid, 2-[(4-chlorophenyl)acetyl] (1.0 eq.) and 1664 ml methanol were also added. The mixture was refluxed during 4 hours. Subsequently, it was cooled to 60 C and 143 g of sodium hydroxide 50% (1.14 eq) were added. The reaction was heated and distilled until a temperature of 100 C to remove the methanol. The mixture was cooled down to 60 C and 2050 ml of isobutylmethylketone (MIBK) and 500 ml of water were added. The aqueous layer was separated. 1750 ml of water and 172 g HCI (36%)(1.1 eq.) were added to the organic layer. The aqueous layer was separated. The organic layer was extracted at the same temperature with 525 ml of water. Some impurities of the process were dissolved in the organic layer. The aqueous layers were combined and 1880 ml of MIBK and 151 g of sodium hydroxide 50% (1.2 eq.) were added. The mixture was maintained 15 min. under stirring and the aqueous layer was separated. The organic layer was treated with charcoal. The treated solution was cooled down to 0-5 C crystallizing a solid. After two hours at 0-5 C, an off solid was filtered-off and washed with MIBK. The wet product was dried under vacuum to yield anhydrous azelastine. Purity by HPLC: 99.8% 1H-RMN (dmso-6d, 400 MHz): 1.59-1.65 (1 H, m), 1.76-2.05 (5H, m), 2.24 (3H, s), 2.44-2.60 (5H, m), 4.32 (2H, s), 5.13-5.21 (1 H, m), 7.35 (4H, s), 7.80 (1 H, td, 7.2 Hz, 1.2 Hz), 7.86 (1 H, td, 8.0 Hz, 1.6 Hz), 7.95 (1 H, d, 8.0 Hz), 8.27 (1 H, dd, /.2 Hz, 1.2 Hz). 13C-RMN (dmso-6d, 100 MHz): 24.8 (t), 32.0 (t), 33.0 (t), 37.1 (t), 46.8 (q), 53.6 (t), 55.3 (d), 58.3 (t), 125.2 (d), 126.6 (d), 127.3 (s), 128.0 (s), 128.4 (d), 130.6 (d), 131.1 (s), 133.2 (d), 137.0 (s), 144.5 (s), 157.2 (s). IR (KBr): 3441, 2962, 2931, 2846, 2789, 1636, 1588, 1493, 1350, 1334, 775. mp: 113.0-114.1C. KF: <0.1 %. The X-ray diffraction analysis gave the diffractogram shown in FIG. 1. The Differential Scanning Calorimetry analysis gave the curve shown in FIG. 2.

2-[(4-Chlorophenyl)acetyl]benzoic Acid is an impurity of Azelastine (A808250).

Molecular Weight:274.70
XLogP3:3
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:4
Exact Mass:274.0396719
Monoisotopic Mass:274.0396719
Topological Polar Surface Area:54.4
Heavy Atom Count:19
Complexity:334
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes