1-(4-(TRIFLUOROMETHOXY)PHENOXY)-4-(METHYLSULFONYL)BENZENE synthesis

Yield:-

Reaction Conditions:

with potassium hydroxide;phosphoric acid in n-heptane;water;dimethyl sulfoxide;acetonitrile;

Steps:

4.A 1-(methylsulfonyl)-4-(4'-(trifluoromethoxy)phenoxy)benzene

EXAMPLE 4A 1-(methylsulfonyl)-4-(4'-(trifluoromethoxy)phenoxy)benzene A solution of 1-fluoro-4-(methylsulfonyl)benzene (2.2 kg), KOH (906.3 g), 4-(trifluoromethoxy)phenol (2.364 kg) and DMSO (4.4 L) was heated to 90° C. and stirred until HPLC showed <0.5% starting material remained (about 10 hours). HPLC conditions: Zorbax SB-C8 4.6 mm*25 cm; mobile phase was a gradient of 70% water with 0.1% H₃PO₄/30% acetonitrile to 10% water with 0.1% H₃PO₄/90% acetonitrile over 15 minutes at a flow rate of 1.5 mL/min, followed by a five minute hold at 10/90; UV detection at 220 nM. Retention times: starting sulfone, 4.5 min; desired product, 7.8 min. The reaction mixture was cooled to room temperature, diluted with water (8.8 kg), and extracted with two portions of toluene (24 L and 4.7 L). The combined extracts were washed with 1N NaOH solution (11 kg) and water (2*11 kg), filtered, concentrated to a volume of approximately 6 L, treated with heptane (22 L) with agitation, stirred for 2 hours, and cooled to 0-5° C. until the mother liquor was assayed for the desired product at <5 mg/mL. The precipitate was filtered, washed with heptane (6.6 L) and dried under vacuum (100 mm Hg with nitrogen sweep) at 40° C. to provide 2.0 kg (96.4% wt potency, 89.6% yield) of the desired product. Recrystallization from methanol/water (4:8 v/v) gave the purified product with 98% recovery. ¹H NMR (300 MHz, CDCl₃) δ 7.9 (d, 2H), 7.3 (br d, 2H), 7.1 (d, 4H), 3.1 (s, 3H).

References:

US2001/31896,2001,A1