Biocatalytic Asymmetric Reduction of a Sterically Hindered α-Bromo Ketone for the Synthesis of Key Intermediates of Olodaterol

IF 3.5 3区化学 Q2 CHEMISTRY, APPLIED

Organic Process Research & Development Pub Date : 2023-03-15 DOI:10.1021/acs.oprd.2c00371

Yahui Feng, Zihong Zhou, Shuming Wu, Wei Lin, Songquan Lu, Xiaolei Pang, Ke Xia, Fang He, Qin Zhang, Hu Yang and Zhongqing Wang*,

{"title":"Biocatalytic Asymmetric Reduction of a Sterically Hindered α-Bromo Ketone for the Synthesis of Key Intermediates of Olodaterol","authors":"Yahui Feng, Zihong Zhou, Shuming Wu, Wei Lin, Songquan Lu, Xiaolei Pang, Ke Xia, Fang He, Qin Zhang, Hu Yang and Zhongqing Wang*, ","doi":"10.1021/acs.oprd.2c00371","DOIUrl":null,"url":null,"abstract":"An efficient and selective biocatalytic process was developed for the reduction of highly bulky and hydrophobic α-bromo ketone 4a using ketoreductase from Lactobacillus kefiri. A fter the initial identification of this selective reductase, reaction conversion was increased from 25.7 to 94.3% and the substrate concentration increased from 5 to 85 g/L via detailed optimization. Through intramolecular epoxidation, the obtained α-bromohydrin 1a was transformed into epoxide 2 as the final product with >99.9% ee, 98.5% HPLC purity, and 90.2% yield over two steps. Eventually, a scale-up demonstration of the telescoped process was successfully performed at a 30 L scale showing excellent reproducibility and consistency, guaranteeing the obtainment of olodaterol with good quality. This biocatalytic process was further demonstrated as environmentally benign by a 50% reduction in process mass intensity (PMI) when compared to the reported (-)-DIP-Cl process.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"27 4","pages":"640–648"},"PeriodicalIF":3.5000,"publicationDate":"2023-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Organic Process Research & Development","FirstCategoryId":"92","ListUrlMain":"https://pubs.acs.org/doi/10.1021/acs.oprd.2c00371","RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, APPLIED","Score":null,"Total":0}

引用次数: 0

Abstract

An efficient and selective biocatalytic process was developed for the reduction of highly bulky and hydrophobic α-bromo ketone 4a using ketoreductase from Lactobacillus kefiri. A fter the initial identification of this selective reductase, reaction conversion was increased from 25.7 to 94.3% and the substrate concentration increased from 5 to 85 g/L via detailed optimization. Through intramolecular epoxidation, the obtained α-bromohydrin 1a was transformed into epoxide 2 as the final product with >99.9% ee, 98.5% HPLC purity, and 90.2% yield over two steps. Eventually, a scale-up demonstration of the telescoped process was successfully performed at a 30 L scale showing excellent reproducibility and consistency, guaranteeing the obtainment of olodaterol with good quality. This biocatalytic process was further demonstrated as environmentally benign by a 50% reduction in process mass intensity (PMI) when compared to the reported (-)-DIP-Cl process.

Abstract Image

查看原文本刊更多论文

位阻α-溴酮生物催化不对称还原合成碘daterol关键中间体

利用kefiri乳杆菌中的酮还原酶，建立了一种高效、选择性的还原高体积疏水性α-溴酮4a的生物催化工艺。在初步鉴定出该选择性还原酶后，经过详细优化，反应转化率从25.7%提高到94.3%，底物浓度从5 g/L提高到85 g/L。通过分子内环氧化反应，得到的α-溴丙烷1a转化为最终产物环氧化物2，两步合成产物ee为99.9%，HPLC纯度为98.5%，收率为90.2%。最后，在30 L的规模下成功地进行了伸缩工艺的放大演示，显示出良好的再现性和一致性，保证了获得高质量的olodaterol。与已报道的(-)- dip - cl工艺相比，该生物催化工艺的质量强度(PMI)降低了50%，进一步证明了该工艺对环境无害。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Organic Process Research & Development 化学-应用化学

CiteScore

6.90

自引率

14.70%

发文量

251

审稿时长

2 months

期刊介绍： The journal Organic Process Research & Development serves as a communication tool between industrial chemists and chemists working in universities and research institutes. As such, it reports original work from the broad field of industrial process chemistry but also presents academic results that are relevant, or potentially relevant, to industrial applications. Process chemistry is the science that enables the safe, environmentally benign and ultimately economical manufacturing of organic compounds that are required in larger amounts to help address the needs of society. Consequently, the Journal encompasses every aspect of organic chemistry, including all aspects of catalysis, synthetic methodology development and synthetic strategy exploration, but also includes aspects from analytical and solid-state chemistry and chemical engineering, such as work-up tools，process safety, or flow-chemistry. The goal of development and optimization of chemical reactions and processes is their transfer to a larger scale; original work describing such studies and the actual implementation on scale is highly relevant to the journal. However, studies on new developments from either industry, research institutes or academia that have not yet been demonstrated on scale, but where an industrial utility can be expected and where the study has addressed important prerequisites for a scale-up and has given confidence into the reliability and practicality of the chemistry, also serve the mission of OPR&D as a communication tool between the different contributors to the field.