4-Piperidinecarboxylic acid, 4-fluoro-1-(phenylMethyl)-, ethyl ester synthesis

Yield:1250443-08-3 66%

Reaction Conditions:

Stage #1: N-benzyl isonipecotic acid ethyl esterwith n-butyllithium;N-ethyl-N,N-diisopropylamine in tetrahydrofuran at -40 - -10; for 1.16667 h;
Stage #2: with N-fluorobis(benzenesulfon)imide in tetrahydrofuran at -78 - -65; for 1.33333 h;

Steps:

X.1

General Procedure X: Nucleophilic fluorination at the a-position of an esterA flask is charged with a base (such as LDA, LiHMDS, NaHMDS, NaOEt, NaOMe, KOtBu, or NaNH₂, preferably LDA) (1 to 3 equiv, preferably 1.5 equiv) in an organic solvent (such as THF, 1 ,4-dioxane, Et₂0 or DMF, preferably THF). The temperature of the mixture is adjusted to about -78 to -30 °C (preferably about -40 °C) and a solution of an ester (preferably 1 equiv) in an organic solvent (such as 1,4-dioxane, THF, Et₂0, or DMF preferably THF) is added slowly so as to maintain the temperature of the mixture within about +/- 10 °C. The mixture is stirred at about -40 to 0 °C (preferably about -15 to -10 °C) for about 30 min to 2 h (preferably about 1 h), and is then cooled to about -78 to -40 °C (preferably about -78 °C). To the mixture is slowly added a solution of A^-fluoro-A^-(phenylsulfonyl)benzenesulfonamide (1-2 equiv, preferably 1.05 equiv) in an organic solvent (such as 1,4-dioxane, THF, Et₂0 or DMF, preferably THF) to maintain the temperature of the mixture within about +/- 15 °C. The resulting mixture is stirred at about -78 to 0 °C (preferably about -78 °C) for about 30 min to 4 h (preferably about 1 h). The mixture is poured into ice water and extracted with an organic solvent (such as DCM or EtOAc). The combined extracts are optionally washed with water and/or brine, dried over anhydrous Na₂S0₄ or MgS0₄, filtered or decanted and concentrated under reduced pressure. The crude material is optionally purified by silica gel chromatography. Illustration of General Procedure XPreparation No.X.l: Ethyl l-benzyl-4-fluoropiperidine-4-carboxylateA flask was charged with DIEA (8.64 mL, 60.6 mmol) and THF (100 mL). The mixture was cooled to about -78 °C followed by the addition of ?-BuLi (24.3 mL, 60.6 mmol) over about 5 min. The mixture was warmed to about 0 °C and stirred for about 30 min and then cooled to about -40 °C. To the mixture was added a solution of ethyl l-benzylpiperidine-4-carboxylate (10.0 g, 40.4 mmol, Oakwood) in THF (75 mL) over about 10 min such that the solution is kept between -40 to -30 °C. The mixture was stirred for about 1 h at about -10 °C before being cooled to about -78 °C. A solution of A^-fluoro-A^-(phenylsulfonyl)benzenesulfonamide (14.0 g, 44.5 mmol) in THF (75 mL) was added over about 20 min while keeping the mixture between about - 65 and -78 °C. The mixture was then stirred for about 1 h at about -78 °C. The mixture was poured into a separatory funnel containing ice water (30 mL) and EtOAc (30 mL) was added. The aqueous layer was extracted with EtOAc (3 x 25 mL) and the combined organic extracts were washed with brine, dried over anhydrous Na₂S0₄, filtered and concentrated under reduced pressure. The resulting mixture was adsorbed onto silica gel and purified by flash silica gel chromatography eluting with hexanes/EtOAc (10:1) to afford ethyl l-benzyl-4-fluoropiperidine-4- carboxylate (7.13 g, 66 %): LC/MS (Table 2, Method h) R_t = 2.21 min; MS m/z: 266 (M+H)⁺.

References:

WO2012/48222,2012,A1 Location in patent:Page/Page column 185-186