N-Boc-4-hydroxypiperidine is a biochemical reagent that can be used as a biological material or organic compound for life science related research. The versatile compound N-Boc-4-Hydroxypiperidine is essential to drug development and pharmaceutical research. This molecule, characterized by its unique structure and reactivity, has become an indispensable tool for chemists and researchers in the pharmaceutical industry. In this comprehensive guide, we'll explore the various applications, benefits, and impacts of this substance in the realm of drug discovery and formulation. One of the primary applications of N-Boc-4-Hydroxypiperidine is in the synthesis of piperidine-based drugs. The piperidine ring, a six-membered heterocycle containing a nitrogen atom, is a common structural motif found in many pharmaceutically active compounds. The presence of the N-Boc protecting group and the hydroxyl functionality at the 4-position provides chemists with multiple options for further modifications and derivatizations.

Normal synthesis of N-BOC-4-Hydroxypiperidine

Tert-Butyl 3,3,5,5-tetradeutero-4-oxopiperidine-l-carboxylate 23 (1.1 g, 5.41 mmol) was dissolved in methanol (10 mL) and cooled to 0 °C with an ice bath. Sodium borohydride (0.2 g) was added as a single portion and the solution was stirred at ambient temperature and pressure for 12h. The reaction was neutralized with aqueous saturated ammonium chloride, volatiles concentrated, and then re -partitioned with water and ethyl acetate. The product was extracted with ethyl acetate. The combined organics were dried over sodium sulfate, filtered and concentrated to give N-BOC-4-Hydroxypiperidine as a colorless oil (0.955 g, 4.65 mmol, 86% yield, >99% D4) 1H NMR (400 MHz, CDC13) δ: 3.84-3.81 (br s, 3H), 2.99 (d, J = 4 Hz, 2H), 1.47 (s, 9H); MS (ESI) 206.2 [(M + H)+].[1]

Efficient Preparation of N-BOC-4-Hydroxypiperidine

Many bioactive molecules and pharmaceutical ingredients have piperidine rings. Among the large number of piperidine-containing molecules, 3-hydroxypiperidine presented in a variety of natural products is identified a privileged scaffold. The hydroxyl group on the C3 position would endow the molecule with chirality and may significantly affect the bioactivity. Though the biocatalysts are atom-economic and environment-friendly, their deficiencies in substrate load/concentration, enantioselectivity, and yield determine that further protein engineering and the development of novel biocatalyst are still required. N-BOC-4-Hydroxypiperidine is an important pharmaceutical intermediate in synthesizing Imbruvica, which is a newly approved drug in lymphoma therapy by targeting Bruton’s tyrosine kinase (BTK). Chemical asymmetric synthesis of (S)-NBHP requires Pb(OH)2 as catalyst and the yield is low. To our knowledge, there is only one report on the biotransformation of N-BOC-4-Hydroxypiperidine; however, the sequence of ketoreductase was not shown and thermodeactivation and substrate inhibition were found in the conversion process, which limits its application in industry.[2]

N-BOC-4-Hydroxypiperidine ((S)-NBHP) is a key pharmaceutical intermediate and the chiral source in synthesizing Imbruvica, which is a newly approved drug in lymphoma therapy by targeting Bruton’s tyrosine kinase (BTK). Current chemical synthesis of N-BOC-4-Hydroxypiperidine suffered from the need of noble metal catalyst and low yield. The single reported bioconversion of (S)-NBHP was achieved by using recombinant ketoreductase, but enzyme sequence was kept confidential and the catalytic process suffered from the thermodeactivation and substrate inhibition. In the current study, we presented a thermostable aldo-keto reductase (AKR)—AKR-43—which showed high activity toward N-Boc-3-piperidone (NBP) to produce N-BOC-4-Hydroxypiperidine, high enantioselectivity, and no substrate inhibition. The molecular simulations demonstrated the structural rationale for the enantioselectivity of AKR-43 toward NBP and supported the classic ordered two-step catalytic mechanism. The catalytic process was achieved by using glucose dehydrogenase (GDH) for cofactor recycling, and the optimal reaction conditions were determined to be 30 °C and pH 7.5. Within a reaction time of 16 h, the 16 % substrate concentration (w/w), over 99 % ee and under 3.5 % of enzyme loading (w/w) characterized a high efficiency process with promising industrial values.

References

[1]Current Patent Assignee: SUN PHARMACEUTICAL INDUSTRIES - WO2014/81816, 2014, A1

[2]He, Mengyan et al. “Efficient Preparation of (S)-N-Boc-3-Hydroxylpiperidine Through Bioreduction by a Thermostable Aldo-KetoReductase.” Applied biochemistry and biotechnology vol. 181,4 (2017): 1304-1313. doi:10.1007/s12010-016-2285-3