4-CARBOXY-2,6-DIFLUOROBENZALDEHYDE synthesis

Yield: 36%

Reaction Conditions:

Stage #1:3,5-difluorobenzoic acid with n-butyllithium;N,N,N,N,-tetramethylethylenediamine in 2-methyltetrahydrofuran;hexane at -78 - -65; for 1.5 h;
Stage #2:Methyl formate in 2-methyltetrahydrofuran;hexane at -78 - 20; for 18.75 h;
Stage #3: with hydrogenchloride in water at 0 - 5;

Steps:

Intermediate compound 32: 3,5-difluoro-4-formylbenzoic acid
To a solution of 3,5-difluorobenzoic acid (20 g, 126.5 mmol) in 2- methyltetrahydrofuran (225 ml_) Ν,Ν,Ν',Ν'-tetramethylethylenediamine (TMEDA) (2.2 eq., 278.3 mmol, 43 ml_) was added at room temperature. The resulting solution was cooled to -78⁵C and "Butyllithium ("BuLi 2.5 M in hexane) (2.5 eq., 316.2 mmol, 126.5 ml_) was added dropwise, during which the temperature of the mixture remained at less than -65⁵C. The mixture was then stirred at -78⁵C for 1 .5 h. Anhydrous methyl formate (2.1 eq., 265.6 mmol, 16.4 ml_) was added dropwise at a rate that allowed the temperature to be maintained at less than - 65⁵C. The resulting solution was allowed to stir at -78⁵C for 45 min, then the bath was removed and the reaction mixture was allowed to warm to room temperature while being stirred for 18h. The mixture was then cooled to 0-5⁵C and excess base was quenched with 6 M aqueous HCI (7 eq., 885.5 mmol, 140 ml_). The phases were then separated, and the aqueous layer was extracted 3 times with ethyl acetate. The combined organic phases were washed with 1 N HCI solution, saturated brine, dried over anhydrous sodium sulphate, filtered and concentrated under vacuum. The residue was triturated in the minimum amount of ethyl acetate. A white solid precipitated was collected by filtration, rinsed with hexanes and dried under vacuum to form the title compound (8.48g, Yield: 36%) as a solid. ¹ H NMR (400 MHz, CDCI₃) δ 10.41 (1 H, s), 7.72 (2H, d, J = 8.4 Hz). ¹ H NMR (400 MHz, DMSO-d₆) δ 13.95 (1 H,s), 10.22 (1 H, s), 7.65 (2H, d, J

References:

ALMIRALL, S.A.;DRACONIS PHARMA, S.L.;LABORATORIOS DEL DR. ESTEVE, S.A.;AGUILAR, Nuria;FERNANDEZ, Joan, Carles;TERRICABRAS, Emma;CARCELLER GONZALEZ, Elena;GARCIA GARCIA, Francisco, Javier;SALAS SOLANA, Jordi WO2013/149996, 2013, A1 Location in patent:Page/Page column 56; 57