4'-Chloropivaloanilide

Reference N-pivaloyl-p-chloroaniline CAB (113 kg, 886 mol), city water (565L), and sodium bicarbonate (89.3 kg, 1.2 eq) were added to ethyl acetate (1695L), and pivaloyl chloride (112 kg, 1.05 eq) was added dropwise thereto at 15°C or lower, and the solution was stirred at about 25°C for 2 hours. After separating the layers, the organic layer was washed with city water (848L x 2), and concentrated under reduced pressure up to about 600L. Ethylcyclohexane (848L) was added thereto, and concentrated again under reduced pressure up to about 600L. The residue was cooled to about 5°C, and stirred to mature for 1 hour. The precipitated crystals were collected by filtration, and dried under reduced pressure to give the title compound (187 kg, yield 99.7percent).Step A2: To a biphasic solution of p-chloroaniline (15 mmol, 1.92 g) in dichloromethane and 10percent aqueous solution of sodium carbonate, pivaloyl chloride (16.5 mmol, 2.03 ml) was added dropwise. The reaction mixture was stirred intensively for 30 min. The reaction progress was followed by TLC. After reaction was completed, organic layer was separated and volatiles removed under reduced pressure to obtain N-(4-chloro-phenyl)-2, 2-dimethyl-propionamide as a white solid in excellent yield (3.1 g, 98percent yield). Step 1: Synthesis of N-(4-chlorophenyl)pivalamide 2 from p-chloroaniline: (0081) 4-Chloroaniline (1 mmol) was added to solution of aqueous NaOH (1.15 mmol in 1.2 times of water) in toluene (4 vol.). The reaction mixture was cooled to 15°C and add pivaloylchloride (1.2 equiv.) slowly by maintaining the temperature below 40°C. The reaction was maintained between 25-35°C for 1 h. After completion of the reaction, it was cooled to - 10°C for 2 h, filtered, washed with 10percent aqueous methanol to afford 98percent of N-(4- chlorophenyl)pivalamide .In the reactor, 40.2 g of p-chloroaniline was charged, 250 mL of toluene, Cooling to 0 ~ 5 , 45.4 g of 30percent sodium hydroxide solution was added, Control temperature in 5 ~ 15 , 41.6 g of pivaloyl chloride was added dropwise, 1 hour drop finished, And then at 5 ~ 15 heat 1 hour, stratified, washed twice organic layer, cooled to -5 , Insulation 2 hours, filtration, filter cake washed, drained, The filter cake was vacuum dried at 70 ° C for 24 hours, To obtain 64.5 g of 4-chloro-N-pivaloanilide, Content of 99.4percentYield 96.8percent.[0107] 4-Chloroaniline (100 g) was dissolved in ethyl acetate (1500 mL), water (500 mL) and sodium hydrogen carbonate (79 g) were added, pivaloylchloride (99 g) was added at 5-15° C., and the mixture was stirred at 20-30° C. for about 2 hr. The mixture was partitioned, and the organic layer was washed twice with water (750 mL) and concentrated to about 500 mL under reduced pressure. Ethylcyclohexane (750 mL) was added, and the mixture was concentrated to about 500 mL. The concentrated residue was cooled to 0-5° C., and the mixture was stirred while aging the crystals at the same temperature for 1 hr. The precipitated crystals were collected by filtration, washed with cold ethylcyclohexane (200 mL), and dried under reduced pressure to give the title compound as crystals. Standard yield: 95±10percent2, 2-dimethylpropionyl chloride (6.3 mL, 51.0 mmol) was added dropwise to a mixture of 4-chlorophenylamine (5 g, 39.2 mmol), EtTo a solution of 4-Chloroaniline (32, 2.592 g, 20.32 mmol) in CHTo 4-Methyl pyrimidine (5.0 g, 0.053 mol) in pyridine (55ML) was added selenium dioxide (8.82 g, 0.079 mol) at RT with stirring. The reaction mixture was stirred at 55 °C for 2 h and at 80 °C for 3.5 hr. After cooling to RT and stirring over night, the reaction mixture was filtered and the residue was washed with pyridine. The combined pyridine solution was concentrated and the carboxylic acid obtained was washed with water to remove traces of selenium dioxide. Yield : 5.3 g, 80.5 percent. [00157] To Pyrimidine-4-carboxylic acid (5.0 g, 0.04 mol) in methanol (170 ml) was added conc. HCI (2 ML) at RT. After refluxing overnight, the reaction mixture was cooled to RT and neutralized with 10 percent sodium bicarbonate solution and concentrated. The ester was extracted with diethyl ether, dried over NA2SO4 AND concentrated to get the methyl ester as a yellow solid, yield : 3.3 g, 57.55 percent. [00158] TRIMETHYL ACETYLCHLORIDE (11.30 g, 0.093 mol) was added to a benzene (500 ML) solution of triethylamine (15.75 g, 0.155 mol) and 4- CHLOROANILINE (10.0 g, 0.078 mol) at 0°C. The reaction mixture was warmed to RT and stirred for 3h. The reaction mixture was then quenched with water, extracted with ethyl acetate, washed with water, brine solution and dried over NA2SO4. The solid product obtained was crystallized from pet ether. Yield : 14.0 g, 84. 43 percent. [00159] To N- (4-chlorophenyl)-2, 2-dimethyl propanamide (3.5 g, 0.0165 mol) in THF (50 MI) at 0 °C was added n-butyl lithium in hexane (2.64 g, 1.2 M, 0. 041 MOL). Stirring was continued at 0 °C for 2 h, the reaction then cooled to-70 °C, pyrimidine-4-methyl carboxylate (3.18 g, 0.023 mol) in THF (25 ML) was then added slowly and the solution was warmed to RT and stirred overnight. Diethyl ether (50 ml) and water (50 ml) were added and the organic layer was separated. The aqueous layer was further extracted with ether. The combined ether layers were washed with water, brine and dried over NA2SO4. The product obtained upon concentration was purified by column chromatography. Yield : 1.7 g, 32.69 percent. [00160] The protected amino ketone (1.7 g, 0.0054 mol) in sulfuric acid (10 ML, 70 percent) was heated at 95 °C over night. The reaction mixture was cooled to RT and basified with 10percent NAOH, extracted with DCM, washed with water, brine and dried over NA2SO4. The product obtained upon concentration was purified by column chromatography using basic alumina to yield title compound (0.20g, 16percent).General procedure: A mixture of Acetylaniline (0.2 mmol), NCS (0.26 mmol), D-CSA (0.1 mmol) and 1, 3-di(1-adamantl)imidazolium tetrafluoroborate (0.01 mmol) in dioxane (1 mL) wasstirred at room temperature (25 oC) under air atmosphere for 24h. The reactionmonitored by GC-MS. When the acetylaniline was consumed completely, the reactionmixture was quenched with saturated aq. NaHCO3 (4 mL). The resulting mixture wasextracted with EtOAc (4 mL x 3). The organic layer was washed with pure water (4ml x 3). The combined organic layer was dried over anhydrous Na2SO4, filtered andthe solvent was removed under reduced pressure to provide the crude product. Thepurification was performed by flash column chromatography on silica gel.

Molecular Weight:211.69
XLogP3:2.6
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:1
Rotatable Bond Count:2
Exact Mass:211.0763918
Monoisotopic Mass:211.0763918
Topological Polar Surface Area:29.1
Heavy Atom Count:14
Complexity:202
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes