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With sulfuric acid; In dichloromethane; at -78 - 20℃;
To 24.9 g of <strong>[431888-57-2]2-chloro-4-(methoxycarbonyl)benzoic acid</strong> and 2 mL of Sulfuric Acid in 350 mL of DCM was added isobutylene gas at -78 C. until the solvent was saturated and capped off securely. Let go several days at room temperature and re-cool to -78 C. before removing cap. Concentrate solvent, extract with Ethyl Acetate and bicarbonate, dry with Magnesium Sulfate, filter and concentrate to give 31.4 g of 1-tert-butyl 4-methyl 2-chloroterephthalate. 3.35 g of 1-tert-butyl 4-methyl 2-chloroterephthalate was hydrolyzed via Procedure M. 2.5 g of 4-(tert-butoxycarbonyl)-3-chlorobenzoic acid was was cooled to 0 C. in 25 mL of THF before a solution of 19.5 mL of 1M BH3-THF complex in THF was added dropwise. The ice bath was subsequently removed and the reaction was stirred at room temperature until reaction stalled out at -50% complete by TLC. The reaction is re-cooled to 0 C. and another 19.5 mL of BH3-THF is added dropwise before the ice bath is removed. Upon completion, the reaction is re-cooled to 0 C. and quenched with 3N HCl dropwise. The aqueous layer was extracted two times with Ethyl Acetate and the organic layer was then extracted once with bicarbonate solution and brine, dried over Magnesium Sulfate, filtered and concentrated to give tert-butyl 2-chloro-4-(hydroxymethyl)benzoate. 564 mg of tert-butyl 2-chloro-4-(hydroxymethyl)benzoate was cooled to 0 C. in 5 mL of DCM before adding 665 mg of Triphenylphosphine and 417 mg of NBS. Reaction was concentrated and directly purified via ISCO Combi-Flash to give pure tert-butyl 2-chloro-4-(hydroxymethyl)benzoate. 147 mg of tert-butyl 4-(bromomethyl)-2-chlorobenzoate was reacted with 2,2,2-trifluoroethanamine in DMSO via Procedure P. 141 mg of tert-butyl 2-chloro-4-((2,2,2-trifluoroethylamino)methyl)benzoate was treated with 4N HCl in Dioxane at 45 C. and concentrated to give 2-chloro-4-((2,2,2-trifluoroethylamino)methyl)benzoic acid. 50 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 75 mg of 2-chloro-4-((2,2,2-trifluoroethylamino)methyl)benzoic acid via Procedure G. The crude product was purified by reverse phase HPLC to give pure 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((2,2,2-trifluoroethylamino)methyl)benzamide. MS (Q1) 454.6 (M)+.
With boron tribromide; In dichloromethane; at -5 - 20℃; for 18.5h;
A solution of dimethyl 2-chloroterephthalate (2.5 g, 1 1 mmol) in DCM (20 mL) was cooled to -5C and treated with BBr3 (1 M in DCM) (1 1 mL, 1 1 mmol) dropwise over 30 min. The mixture was then warmed to RT and stirred for 18 h. The mixture was poured into ice, warmed to RT and the pH was adjusted to 8 by the addition of solid NaHC03. The aq. solution was washed with EtOAc (50 mL), acidified by the addition of 1 M HCI and extracted with EtOAc (160 mL). The organic solution was washed with brine (80 mL), dried over MgS04, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (120 g, 0-10% [MeOH 5% AcOH] in DCM) to afford the title compound (2) (1.5 g, 62%) as white solid: m/z 215 [M+H]+ (ES+), 213 [M-H]- (ES-); NMR (400 MHz, DMSO-de) delta: 13.79 (1 H, br. s), 8.00 - 7.95 (2H, m), 7.90 - 7.88 (1 H, m), 3.89 (3H, s)
With boron tribromide; In dichloromethane; at 0 - 20℃;
20 g of dimethyl 2-chloroterephthalate was cooled to 0C in DCM and 87 mL of a IM in DCM solution Of BBr3 was added dropwise over several hours. The reaction mixture was subsequently warmed to room temperature and stirred until complete. Following basic workup, 2-chloro-4-(methoxycarbonyl)benzoic acid was purified by ISCO Combi-Flash.
With boron tribromide; In dichloromethane; at 0 - 20℃;
67 mL of 2-chloro-1,4-dimethylbenzene and 356 g of Potassium Permanganate were refluxed in 1.5 L of H2O for several hours and monitored for disappearance of starting material by TLC. The Potassium Permanganate was filtered and the reaction mixture was acidified and filtered to yield 2-chloroterephthalic acid. 46.8 g of 2-chloroterephthalic acid was treated with a saturated HCl gas solution in MeOH overnight at room temperature. The reaction mixture was concentrated, subjected to basic workup and dried to yield the dimethyl 2-chloroterephthalate. 20 g of dimethyl 2-chloroterephthalate was cooled to 0 C. in DCM and 87 mL of a 1 M in DCM solution of BBr3 was added dropwise over several hours. The reaction mixture was subsequently warmed to room temperature and stirred until complete. Following basic workup, 2-chloro-4-(methoxycarbonyl)benzoic acid was purified by ISCO Combi-Flash. 959 mg of 2-chloro-4-(methoxycarbonyl)benzoic acid was coupled to 750 mg of 4-chloro-3-(pyridin-2-yl)aniline via procedure G. 1 g of methyl 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoate was hydrolyzed via Procedure M to give 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid. 50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to tert-butylamine via Procedure G. The product was purified on reverse phase HPLC to yield N4-tert-butyl-2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)terephthalamide. MS (Q1) 443.2 (M)+.
4-methyl 2-chloro-1,4-benzenedicarboxylate (B) STR11 Acidification of product from Example 4 with 10% hydrochloric acid gives the titled acids.
4
[ 431888-57-2 ]
[ 115-11-7 ]
[ 431888-58-3 ]
Yield
Reaction Conditions
Operation in experiment
With sulfuric acid; In dichloromethane; at -78 - 20℃;
To 24.9 g of <strong>[431888-57-2]2-chloro-4-(methoxycarbonyl)benzoic acid</strong> and 2 mL of Sulfuric Acid in 350 mL of DCM was added isobutylene gas at -78C until the solvent was saturated and capped off securely. Let go several days at room temperature and re -cool to -78C before removing cap. Concentrate solvent, extract with Ethyl Acetate and bicarbonate, dry with Magnesium Sulfate, filter and concentrate to give 31.4 g of 1-tert-butyl 4-methyl 2-chloroterephthalate.
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