(1’S,2S)-2-(1’,2’-Dihydroxyethyl)-6-fluorochromane synthesis

Yield:4.762 % de

Reaction Conditions:

with sodium tetrahydroborate in tetrahydrofuran;hexane at 20; for 0.5 h;Inert atmosphere;Overall yield = 18 g;

Steps:

2 Synthesis of (S)-1-(6-fluorochroman-2-yl)ethane-1,2-diol semichiral diols

To a solution of (S)-ethyl 6-fluorochroman-2-carboxylate) (18 g, 80.3 mmol) and dibromomethane (12.6 mL) in anhydrous THF (360 mL) cooled to -100°C under nitrogen atmosphere, a solution of 1.6 M BuLi in hexane (101 mL) , cooled beforehand to -78°C, was added dropwise, in a time of 30 min. Stirring was maintained at -100°C for 1.5 h in total, until disappearance of the ester substrate (TLC control). Then, a 0. IN NaHSO₄ solution (40 mL) was added at the same temperature. At the end of the addition, temperature was slowly brought to -30/-20°C and it was stirred for 30-50 min. Then, NaBH₄ (2.5 g) was added and the resulting mixture mixed until complete reduction of the intermediate alpha-hydroxy ketone to diol (about 0.5 h) . 1N NaHSO4 was added to the mixture, up to pH 5, the organic phase was separated and the aqueous phase extracted with EtOAc. The reunited organic extracts were washed with water, dried over Na₂SO4, filtered and concentrated under reduced pressure to obtain a yellow and viscous fluid (18 g) . HPLC analysis showed a 1.1:1.0 ratio of the two (SR:SS) diastereoisomeric diols (6). Analogously to what described in example 2, the (RS:RR) diols 5 were obtained starting from (R)-ethyl 6- fluorochroman-2-carboxylate).

References:

WO2013/18053,2013,A1 Location in patent:Page/Page column 19; 20