3-CHLORO-2-FLUORO-5-(TRIFLUOROMETHYL)BENZOYL CHLORIDE synthesis

Yield:-

Reaction Conditions:

with oxalyl dichloride;N,N-dimethyl-formamide in toluene at 20; for 0.5 h;Product distribution / selectivity;Inert atmosphere;

Steps:

5.1
Example 5.1: Synthesis of N-(4-tert-butyl-benzyl)-3-chloro-N-[2-(4-chloro-3-ethyl- phenyl)-ethyl]-2-fluoro-5-trifluoromethyl-benzamide To a solution of 2-Fluoro-3-chloro-5-trifluoromethyl-benzoic acid (33.9 g, 135.6 mmol, 1.2eq.) in toluene (450 ml) was added under Ar in apparatus A at RT and under vigorous stirring DMF (1.7 ml, 22.0 mmol, 0.195 eq.) and oxalyl chloride (16.0 g, 123.5 mmol, 1.09 eq.) and the reaction mixture was stirred for 30 min. This reaction mixture was added at an internal temperature of 20-35 °C to a previously prepared suspension (in Apparatus B) of (4- tert-butyl-benzyl)-[2-(4-chloro-3-ethyl-phenyl)-ethyl]-amine hydrochloride (41.5 g, 113.0 mmol), toluene (600 ml) and triethyl amine (66.7 ml, 467.8 mmol, 4.22 eq.). The Apparatus A was rinsed with toluene (20 ml), the white suspension was stirred for 1 h at RT and the filter cake was washed portionwise with toluene (300 ml). The filtrate was extracted sequentially with water (500 ml), HCl (1 M, 500 ml), NaHC0₃ (saturated, 500 ml) and water (500 ml) and the organic phase was evaporated to dryness under vacuum. The oil was dissolved at 45°C in 2-propanol (200 ml) and water (13.5 ml) was added. The solution was cooled to 25 °C within 2 h, seeding crystals were added and at RT water (27 ml) was added. The suspension was stirred for 5 h at RT and 1 h in an ice bath, the white crystals were filtered off, washed portionwise with ice-cold 2-propanol/water (4:1) and the crystals were dried under vacuum at 50°C to give the title compound (57.3 g, 91.2 % of theory) as white crystals. MS (EI): m/z= 554 ([M+H]⁺, 100%).

References:

F. HOFFMANN-LA ROCHE AG;BACHMANN, Stephan;BLISS, Fritz;DIODONE, Ralph;HILDBRAND, Stefan;KAMMERER, Michael;PFLEGER, Christophe;REENTS, Reinhard;SCALONE, Michelangelo WO2011/157670, 2011, A2 Location in patent:Page/Page column 37-38