di-tert-butyl (2S,5S)-5-hydroxypiperidine-1,2-dicarboxylate synthesis

Yield:-

Reaction Conditions:

Stage #1: (S)-di-tert-butyl-5-oxopiperidine-1,2-dicarboxylatewith methanol;lithium borohydride in tetrahydrofuran at -10 - 20;
Stage #2: with acetic acid in tetrahydrofuran;methanol at 0 - 20;

Steps:

1.5

To a 1 L 3 -neck round bottom flask equipped with overhead stirring, nitrogen inlet, and thermocouple was charged 264 mL THF, 3 mL MeOH₅ and 73.5 mL of 2M LiBH4 in THF (147 mmol) at room temperature and aged for 30 minutes. The solution was then cooled to -10⁰C and (S)~5-oxo-piperidine-l,2-dicarboxylic acid di-fer/-butyl ester was added as a 4 mL/g solution in THF (44 g., 147 mmol, 176 mL THF) keeping the internal temperature below -5 ⁰C. The addition took 40 minutes. After one hour at 0⁰C TLC showed the reaction to be complete. Meanwhile a 20% acetic acid in MeOH solution was prepared by adding 40 mL of acetic acid to 16O mL MeOH. This solution was transferred to an addition funnel. While keeping the internal temperature below 0 ⁰C 20 mL of the acetic acid/MeOH solution was added watching for excess gas evolution. The solution was aged for 30 minutes, and then warmed to room temperature at which point the rest of the acetic acid/MeOH solution was added keeping the internal temperature below 25 ⁰C. The mixture was then aged for one hour. Water (500 mL) and IPAc (500 mL) was added and transferred to a 2 L separatory funnel. The aqueous layer was cut and the or games was washed twice with 500 mL water and once with 500 mL saturated sodium bicarbonate. The organics were dried with MgSθ4 and concentrated to a dark tan oil and taken on to the next step without further purification. NMR with internal standard showed 35 g. (116 mmol, 79% yield over two steps) of alcohol. lH NMR (500 MHz, CDCI3): δ 4.75 (bs, 0.5H), 4.55 (bs, 0.5H), 4.05-4.3 (m, IH), 3.65 (bs, IH), 2.75 (m, IH), 2.3 (bs, IH), 2.0 (m, IH), 1.7 (bt, IH), 1.5 (s, 19H).

References:

WO2010/126820,2010,A2 Location in patent:Page/Page column 30