(5-(TRIFLUOROMETHYL)PYRIDINE-2,3-DIYL)DIMETHANOL synthesis

Yield:905273-63-4 76.9%

Reaction Conditions:

Stage #1: diethyl 5-(trifluoromethyl)pyridine-2,3-dicarboxylatewith sodium tetrahydroborate;ethanol;magnesium chloride in tetrahydrofuran at 10 - 32; for 14.5 - 15 h;
Stage #2: with water;sodium hydrogencarbonate in tetrahydrofuran;ethanol; for 0.6 h;

Steps:

2.1

A suspension of MgCl₂ (1.63 kg, 16.8 mol) in THF (14.5 L) was treated at T_imax=10° C. over 35 min with EtOH (11.8 L) (exothermic reaction). The reaction mixture was vigorously stirred and treated in portions (over 30-60 min, temperature controlled) with a suspension of sodium borohydride (1.3 kg, 32.99 mol) in THF (6.7 L). A very exothermic reaction ensued, accompanied by foaming. The mixture was warmed to 28° C. and stirred at this temperature over 20 min. To the suspension was added over 35 min at T_i=27-32° C. (T_i=internal temperature) a solution of 2,3-pyridine dicarboxylic acid-5-trifluoromethyl diethyl ester (1.69 kg, 5.7 mol) in EtOH (5.1 L). The yellow-orange suspension was stirred for 13 h at T_i=27-32° C.The yellow reaction mixture was added in portions over 18 min to a solution of NaHCO₃ (5.9 kg, 81.9 mol) and H₂O (68 L) resulting in an exothermic reaction and gas evolution. The yellow suspension was stirred for 18 min, then all of the organic solvent was removed by evaporation under reduced pressure (400-50 mbar) at 60° C. The total volume was adjusted with water to 70 L. The suspension was treated under vigorous stirring with citric acid (10.5 kg, 54.3 mol) dissolved in H₂O (8.4 L) to adjust the pH to 7 (foaming). To the yellow solution was added 40 l tert-butyl methyl ether. After extraction and phase separation, the water phase was extracted twice with tert-butyl methyl ether (30 L, 60 Lin total). The combined organic phases were dried (15 kg Na₂SO₄), filtered and evaporated at 60° C. and 750-10 mbar to afford 913.0 g (76.9%) of (2-hydroxymethyl-5-trifluoromethyl-pyridin-3-yl)-methanol as a yellow-red oil: MS (EI): 208 (M+H⁺, 13), 289 (54), 161 (100).

References:

US2009/143589,2009,A1 Location in patent:Page/Page column 5