143900-44-1Relevant articles and documents
Efficient bioreductive production of (S)-N-Boc-3-hydroxypiperidine using ketoreductase ChKRED03
Xu, Guang-Peng,Wang, Hai-Bo,Wu, Zhong-Liu
, p. 881 - 885 (2016)
Ibrutinib is an anticancer drug targeting B-cell malignancies. The key chiral intermediate for ibrutinib synthesis is the alcohol (S)-N-Boc-3-hydroxypiperidine ((S)-NBHP), which can be produced via ketoreductase (KRED)-catalyzed bioreduction. After screening a small inventory of 27 KREDs mined from the genome of Chryseobacterium sp. CA49, ChKRED03 was selected as the best performer, leading to the complete conversion of 100 g substrate/L within 10 h to yield (S)-NBHP with high enantiomeric excess (> 99% ee). The enzyme was NADPH dependent, and the highest enzymatic activity was observed at 30 °C in potassium phosphate buffer (pH 7.0). At a substrate/catalyst ratio of 66.7 (w/w), ChKRED03 catalyzed the complete conversion of 200 g/L substrate within 3 h to yield (S)-NBHP with >99% ee, demonstrating great potential for industrial application.
Efficient synthesis of Ibrutinib chiral intermediate in high space-time yield by recombinant E. coli co-expressing alcohol dehydrogenase and glucose dehydrogenase
Chen, Yitong,Ma, Baodi,Cao, Songshuang,Wu, Xiaomei,Xu, Yi
, p. 2325 - 2331 (2019)
The production of (S)-N-boc-3-hydroxy piperidine (NBHP) via asymmetric bioreduction of 1-boc-3-piperidinone with reductase is impeded by the need for expensive coenzymes NAD(P)H. In order to regenerate the coenzyme in situ, the gene of alcohol dehydrogenase from Thermoanaerobacter brockii and glucose dehydrogenase from Bacillus subtilis were ligated into the multiple cloning sites of pRSFDuet-1 plasmid to construct the recombinant Escherichia BL21 (DE3) that co-expressing alcohol dehydrogenase and glucose dehydrogenase. Different culture conditions including the medium composition, inducer and pH etc were systematically investigated to improve the enzyme production. The enzyme activity was increased more than 11-fold under optimal culture condition, from 12.7 to 139.8 U L?1. In the further work, the asymmetric reduction of 1-boc-3-piperidinone by whole cells of recombinant E. coli was systematic optimized to increase the substrate concentration and reaction efficiency. At last, S-NBHP (>99% ee) was prepared at 500 mM substrate concentration without external addition of cofactors. The conversion of S-NBHP reached 96.2% within merely 3 h, corresponding a high space-time yield around 774 g L?1 d?1. All these results demonstrated the potential of recombinant E. coli BL21 (DE3) coupled expressing alcohol dehydrogenase and glucose dehydrogenase for efficient synthesis of S-NBHP.
Preparation method of N-tert-butyloxycarbonyl-3-piperidone and derivative thereof
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, (2020/07/21)
The invention discloses a preparation method of N-tert-butyloxycarbonyl-3-piperidone, and the method comprises the following step: oxidizing N-tert-butyloxycarbonyl-3-hydroxypiperidine by virtue of aNaDCC-TEMPO system so as to generate N-tert-butyloxycarbonyl-3-piperidone. The invention also discloses a method for preparing (S)-N-tert-butyloxycarbonyl-3-hydroxypiperidine through an oxidation reaction and a reduction reaction by virtue of the NaDCC-TEMPO system. The method has the advantages of simple operation steps, high conversion rate and high product purity.
PROCESSES AND INTERMEDIATES FOR PREPARING A BTK INHIBITOR
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Page/Page column 15; 16, (2018/04/21)
Disclosed is a process for the preparation of certain intermediates, e.g. the following compound: (I) which intermediate and processes are useful in the preparation of a BTK inhibitor, such as ibrutinib.