2-Methyl-2-[(5-trifluoromethylpyridin-2-yl)oxy]propionic acid synthesis

Yield:-

Reaction Conditions:

Stage #1: ethyl 2-methyl-2-{[5-(trifluoromethyl)pyridin-2-yl]oxy}propanoatewith sodium hydroxide;water in tetrahydrofuran; for 22 h;Heating / reflux;
Stage #2: with hydrogenchloride in water; for 0.166667 h;

Steps:

14

REFERENCE EXAMPLE 14; 2-Methyl-2-(5-trifluoromethyl-2-pyridyloxy)propionic Acid; Two nitrogen flushed, 12 L 3- necked round bottom flasks, each fitted with a thermometer and a reflux condenser were charged with KHMDS in THF (0.91 M, 3.52 L each, 3.205 mol, 1.5 eq). The solutions were cooled to - 70⁰C and stirred magnetically. Ethyl-2-hydroxyisobutyrate (98%) (463 mL, 447g, 3.38 mol) was added to each flask over 30 min, keeping the reaction temperature below ~62°C. After 10 min 2- chloro-5-trifluo?nethylpyridine (388 g, 2.14 mol) was added to each flask in one portion. The cooling bath was removed and the reactions were allowed to warm to 20⁰C overnight (ca 16 hr.).The reactions were monitored by TLC (silica, 90/10 Hex/EtOAc) and HPLC: Sodium hydroxide (1.36 L, 5N) was added to each reaction flask and the reactions were refluxed overnight (ca 22 hr). The reactions were concentrated together on a rotary evaporator to remove the THF. To the concentrate was added water (4L) and the solution extracted with n- heptane (2 x 4L). The aqueous layer was added over 10 min to 2N HCl (9L, 18 mol) with stirring. The resulting suspension was aged for 30 min (temperature 30⁰C) then filtered. The cake was washed with water (3 x 2L), and air-dried to a damp tan solid.The material was dissolved in n-heptane (4 L) at 65⁰C. BPAc (1 L) and DARCO KB (40 g, 100 mesh) were added. The mixture was stirrer for 15 min, filtered through CELITE diatomaceous earth, and the cake washed with 4:1 heptane/IP Ac (3 x 500 mL). The filtrate was concentrated to ca. 2 L affording a white suspension. The slurry was flushed with heptane (2 x 3L) and concentrated to ca. 3L. The resulting white suspension was cooled to O⁰C and aged 1 hr. The product was filtered and the cake washed with cold heptane (1 L) to provide the title compound as white crystalline material. HPLC Column: YMC Combiscreen Pro Cl 8, 50 x 4.6mm; Mobile phase: A 0.1%TFA in H₂O; B CH₃CN. Gradient: 90/10 A/B to 10/90 A/B in 4 min. Flow rate: 4 mL/min. Detection: 254 run. Rt 2-chloro-5-trifluormethylpyridine 2.1 min. Rt 2-ethoxy-5-trifluoromethylpyridine 2.9 min. Rt Product Ester 3.1 min. Rt Final Acid 2.05 min

References:

WO2007/136571,2007,A1 Location in patent:Page/Page column 44-45