Biocatalytic Asymmetric Reduction of a Sterically Hindered α-Bromo Ketone for the Synthesis of Key Intermediates of Olodaterol,Organic Process Research & Development

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Biocatalytic Asymmetric Reduction of a Sterically Hindered α-Bromo Ketone for the Synthesis of Key Intermediates of Olodaterol
Organic Process Research & Development ( IF 3.1 ) Pub Date : 2023-03-15 , DOI: 10.1021/acs.oprd.2c00371
Yahui Feng _{1,

2} , Zihong Zhou _{1,

2,

3} , Shuming Wu _{1,

2} , Wei Lin ₂ , Songquan Lu ₂ , Xiaolei Pang ₂ , Ke Xia ₂ , Fang He ₂ , Qin Zhang _{2,

4} , Hu Yang ₂ , Zhongqing Wang _{1,

2,

5}

Affiliation

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.

中文翻译：

空间位阻 α-溴酮的生物催化不对称还原合成关键中间体奥达特罗

使用来自凯菲里乳杆菌的酮还原酶，开发了一种有效且选择性的生物催化过程，用于减少体积庞大且疏水的 α-溴代酮4a。在初步鉴定出这种选择性还原酶后，通过详细优化，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，将得到的α-溴醇1a转化为环氧化物2作为最终产品，具有 >99.9% ee、98.5% HPLC 纯度和 90.2% 两步收率。最终，在 30 L 规模上成功进行了伸缩过程的放大演示，显示出出色的重现性和一致性，保证了获得高质量的奥达特罗。与报道的 (-)-DIP-Cl 工艺相比，该生物催化工艺通过工艺质量强度 (PMI) 降低 50% 进一步证明对环境无害。

更新日期：2023-03-15

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