Yield:72617-81-3 93%

Reaction Conditions:

Stage #1: 2,2,2-trifluoroethanolwith sodium hydride in N,N-dimethyl-formamide;mineral oil at 0; for 1.33333 h;
Stage #2: 2-chloro-5-nitropyridine in N,N-dimethyl-formamide;mineral oil at 0 - 20; for 2.5 h;

Steps:

108.1

Example 108(5a,8a)-8-Hydroxy-8-isopropyl-2-(6-(2,2,2-trifiuoroethoxy)pyridin-3-yl)- spiro [4.5] decan- 1 -oneStep 1: 5-Nitro-2-(2₁2₁2-trifluoro-ethoxy)-pyridineIn a 250 mL four-necked flask, sodiumhydride (60 % in mineral oil, 4.16 g) was combined with DMF (60mL). The suspension was cooled to 0°C and 2,2,2-trifluoroethanol (10.4 g, [CAS Reg. No. 75-89-8]) was added dropwise over a period of 20 minutes to the cold suspension. The mixture was stirred for 1 hour at 0°C. Then, a solution of 2-chloro-5- nitropyridine (15 g, [CAS Reg. No. 4548-45-2]) in DMF (70mL) was added dropwise over a period of 20 minutes to the cold reaction mixture. Stirring was continued for 10 minutes at 0°C and for 2 hours at r.t.. The reaction mixture was poured into ice/water and was then extracted two times with ethyl acetate. The combined organic layers were washed with brine, dried over Na₂S0₄, and filtered. The solvent was evaporated and the residue was purified by flash chromatography (silica gel, gradient of heptane in ethyl acetate) to give the title compound as a yellow solid (20.52g, 93%). MS (EI, m/e): 222.0 [M⁺].

References:

WO2011/45292,2011,A1 Location in patent:Page/Page column 175-176