2-[4-(Boc-aMino)-3-pyridyl]ethanol synthesis

Yield:219834-80-7 36%

Reaction Conditions:

Stage #1: N-(4-pyridyl) t-butyl carbamatewith tert.-butyl lithium in tetrahydrofuran;pentane at -78 - -15; for 2.4 h;
Stage #2: 2-bromoethanolwith n-butyllithium in tetrahydrofuran;hexane;pentane at 20; for 2 h;

Steps:

9 EXAMPLE 9, METHODS

[00199] Synthesis of tert-butyl N~[3~(2-hydroxyethy])pyridm~4~y]j carbamate (11): Adapted from Spivey et at To a solution of 4-(Boc-amino)pyridme (1) (2.0 g, 10.3 mmol, 1 eq.) in 25 mL of dry THF at -78 °C was added /-Bu f .i (14.5 mL, 1.7 M, 24.7 mmol, 2.4 eq.) in pentane over 30 min. The resulting bright yellow suspension was stirred at -78 °C for 15 mi , at -15 °C for 2h and the recooled to -78 °C, I a separate flask, n-BuLi (7.38 mL, 2.5M. 18.54 mmol, 1 .8 eq) in hexanes was added to a solution of 2-bromocfhanol (1.294 mL, 15.45 mmol, 1.5 eq) in 20 mL of dry THF at -78 °C and stirred for 10 min. After 10 min, the bromoethanol solution was transferred ^"via cannula to the flask containing lithiated N-boc-4- aminopyridine over 10 min. The reaction was allowed to warm to room temperature and the mixture was stirred for 2h. The reaction was recooled to -78 °C and quenched with 5 ml, of water. The solution was partitioned between water (20 mL) and CH₂CI₂ (30 mL). The phases were separated and the extraction was completed with additional portions of CH₂C1₂. The combined organic extracts were washed with brine, dried over MgS0₄ and evaporated under vacuum. The crude product was dissolved in a small amount of€{ purified by silica gel chromatography (EtOAc) to afford the product 11 (0.678 g, 36% yield). R_f = 0.15 (EtOAc). -Ν ΙΙ (500 MHz, CDCI₃) δ: 1.51 (9H, s), 2.81 (2H, t, J ------ 5.0 Hz), 3.80 (1 H, br s), 3.94 (2H, t, J= 5.0 Hz), 7.92 (1H, d, J= 5.5 Hz), 8.15 (1H, s), 8.27 flH, d, J= 5.5 Hz), 8.63 (1H, s).

References:

WO2013/173746,2013,A2 Location in patent:Paragraph 00199