Preparation of (S)-N-BOC-2-piperidinemethanol_Industrial additives

Background and overview^[1-3]

(S)-N-BOC-2-piperidinemethanol is an organic intermediate, which can be composed of N-Boc-L-piperidine-2-carboxylic acid and borane tetrahydrofuran complex or dimethyl sulfide complex It can be obtained by reducing the compound, or by reducing (S)-2-methyl carbonate piperidine-1-tert-butyl carbonate with lithium aluminum tetrahydride.

Preparation^[1-3]

Report 1,

Dissolve compound N-Boc-L-piperidine-2-carboxylic acid (10.0g, 46.6mmol) in THF (100mL), and slowly drop borane (100mL, 1MinTHF) under nitrogen protection at 0°C. In the reaction bottle, complete the dripping and react at constant temperature for 3 hours. After the reaction was complete, the reaction was quenched with methanol (80 mL), the reaction solution was concentrated and purified by column chromatography (eluent: PE/EtOAc (v/v)=3/2) to obtain 7.04g of colorless oil, product Rate: 75.2%. ¹HNMR (MHz, CDCl₃): δ3.99-3.87(br,1H),3.68-3.51(m,2H),3.48-3.39(m,1H ),3.34-3.25(m,1H),2.05-1.92(m,2H),1.88-1.71(m,2H),1.45(s,9H)ppm.

Report 2,

A solution of (S)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (18.5 g, 80.7 mmol) in anhydrous THF (44.4 mL) was cooled to 0°C. BH₃.Me₂S (44.4 mL, 88.8 mmol) was added dropwise over 15 minutes. After the addition is complete, the mixture is warmed to room temperature and stirring with reactive diluent is continued for 18 hours. The mixture was quenched with water and extracted with ethyl acetate. The organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated. Flash chromatography of the resulting residue on silica gel (35% ethyl acetate in hexanes) afforded (S)-N-BOC-2-piperidinemethanol (14.2 g, 82 %). MS116(MH+-boc)

Report 3,

Add lithium aluminum hydride (38 mg, 1 mmol) into a dry tetrahydrofuran solution (10 mL) dissolved in (S)-2-methyl carbonate, piperidine-1-tert-butyl carbonate (1 mmol), and stir at room temperature overnight. Water (0.5 mL) was added to quench the reaction, the solvent was removed under reduced pressure, and the residue was separated by flash column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain (S)-N-BOC-2-piperidinemethanol.

References

[1][Invented in China, Authorized by China Invention] CN201310 Aminosilicone Oil Emulsion 711751.X Spirocyclic compound as a hepatitis C inhibitor and its application in medicine

[2][China invention, China invention authorization] CN201310056066.8 benzimidazole-2-piperazine compound, its pharmaceutical composition and its preparation method and use