Manufacture of chiral amines using catalytic and flow processing methods

手性胺是40%的医药产品和20%的农作物保护化合物的重要组成部分，也是高价值的化学中间体。然而，目前的制造方法效率低、浪费大，而且常常不适合复杂的结构。特别是，合作的最终用户发现缺乏制备仲和杂环手性胺的好方法。通常的方法采用对映体拆分（最大产率50%），这增加了加工步骤和成本。事实上，ASC制药圆桌会议已经将这类反应列为最重要的解决方案之一，并将连续处理列为关键绿色工程研究领域的头号目标。Blacker和Xiao研究并发表了手性胺工艺，他们采用间歇工艺，但没有采用流动工艺。工艺中催化剂的分离及其成本阻碍了工业采用。利兹团队负责测试、工艺开发和放大/缩小多达5种不同的工艺，以制备纯手性仲或叔杂环胺（WP 2）。这些研究需要在利物浦（WP 1）和YPT（WP 3）生产的固体载体催化剂（Cp-Star）和配体，利兹将在iPRD工艺实验室已经开发的流动工艺设备或AMT（WP 4）开发并转移到利兹的淤浆反应器中测试这些催化剂和配体。起始物料和分析方法将由合作的最终用户公司（AZ、辉瑞、先正达和Dr Reddys）提供（WP 5），利兹公司生成的有关产品质量、成本和生产率的工艺数据将用于与现有手性胺生产的不良方法进行比较。制备纯手性胺的方法有：（a）不对称还原胺化（催化剂在利物浦开发，如果需要，利兹可以进行放大）;（B）不对称转移氢化;（c）通过固定化酶拆分胺DKR，连续产物分离和Cp-星形催化外消旋再循环（d）结晶诱导的不对称转化，包括手性胺结晶和母液的催化外消旋（e）使用氢借用对映选择性烷基化胺的氧化还原中性胺烷基化。工业所需的手性胺是杂环仲胺和叔胺，如哌啶、哌嗪、吡咯烷、吲哚啉等。在该项目中，公司将提供各类手性胺的真实的实例，以说明该技术的潜力。流动法的使用方便了多种化合物的筛选，将使用的流动反应器是固定床和滴流床，级联CSTR和由AMT设计并转移到利兹进行评估的新型浆料反应器。这些反应器都是中型的，这是产生适合放大生产的数据所必需的。工作的可测量输出是对映体选择性、转化率、产率、动力学和反应速率、质量平衡（即绿色指标，例如工艺效率和废物）、生产率、制造工艺成本预测（原材料、运营和资本）。这些数据将与现有的工艺进行比较，以相同的产品，使成本效益分析，从而实现本项目的主要目标的一部分.

Chiral amines are important building blocks used in 40% of pharmaceutical products and 20% crop protection compoundsand are high value chemical intermediates. However, current methods of manufacture are inefficient, wasteful, and oftenunsuitable for complex structures. In particular, a lack of good methods to make secondary and heterocyclic chiral amineswas identified by the collaborating end users. The usual processes employ enantiomer resolution (50% max yield), whichadds processing steps and costs. In fact, the ASC pharmaceutical roundtable has listed this class of reactions as one of themost important to solve, and continuous processing as the No 1 target in the key green engineeing reseacrh areas. Thechiral amine processes have all been studied and published by Blacker and Xiao using batch processing but not in flow.Separation of the catalyst and its cost within the processes have prevented industry adoption. These issues will beovercome in the current project using the Cp-star catalysts in flow.The Leeds team is responsible for the testing, process development and scale-up/out of up to 5 different processes tomake homochiral secondary or tertiary heterocyclic amines (WP2). The studies require solid supported catalysts (Cp-Star)and ligands generated at Liverpool (WP1) and YPT (WP3) and Leeds will test these in flow process equipment already inthe iPRD process lab, or slurry reactors developed and transferred to Leeds by AMT (WP4). The starting materials andanalytical methods will be supplied by the collaborating end-user companies (AZ, Pfizer, Syngenta and Dr Reddys)(WP5)and the process data Leeds generates on product quality, cost, productivity will be used to compare with existing poormethods for chiral amine manufacture. The processes to make homochiral amines are: (a) asymmetric reductive amination(catalyst being developed at Liverpool, Leeds can undertake scale-up if required); (b) asymmetric transfer hydrogenation;(c) amine DKR by immobilised enzyme resolution, continuous product separation and Cp-star catalysed racemisationrecycle(d) crystallisation induced asymmetric transformation involving chiral amine crystallisation and catalysedracemisation of the mother liquors (e) redox-neutral amine alkylation using hydrogen borrowing enantioselectively alkylateamines. The chiral amines required by industry are heterocyclic secondary and tertiary amines such as piperidine,piperazine, pyrrolidies, indolines etc. Within the project the companies will supply real examples of each class of chiralamine to illustrate the potential for this technology. The use of flow methodology facilitates screening of multiplecompounds.The flow reactors that will be used are fixed and trickle bed, cascade CSTR and the novel slurry reactors that are beingdesigned by AMT and transferred to Leeds for evaluation in these systems. The reactors are all meso-scale which isrequired to generate data suitable for scale-up to manufacture. The measurable outputs of the work are entantioselectivity,conversion, yield, kinetics and reation rate, mass balance (ie green metrics eg process efficiency and waste), productivity,manufacturing process cost prediction (raw material, operational and capital). This data will be compared with existingprocesses to the same products to enable cost benefit analysis thereby achieve the main objective of this part of theproject.