Manufacture of chiral amines using catalytic and flow processing methods

手性胺是40%的医药产品和20%的植保化合物的重要组成部分，是高价值的化学中间体。然而，目前的制造方法效率低、浪费，而且往往不适合复杂的结构。特别是，合作的最终用户发现，缺乏制造二次环手性胺和杂环手性胺的好方法。通常的工艺采用对映体拆分(最高产率为50%)，这需要处理步骤和成本。事实上，ASC制药圆桌会议已将这类反应列为需要解决的最重要的反应之一，并将连续加工列为关键绿色工程研究领域的头号目标。布莱克和肖都研究和发表了手性胺工艺，他们都是使用间歇工艺，但没有在流程中进行。工艺中催化剂及其成本的分离阻碍了工业应用。这些问题将在目前的项目中使用流动中的CP-STAR催化剂来克服。利兹团队负责测试、工艺开发和放大/扩展至多5种不同的工艺，以制造均手性二或三级杂环胺(WP2)。这项研究需要利物浦(WP1)和YPT(WP3)产生的固体负载型催化剂(CP-Star)和配体，利兹将在iPRD工艺实验室已有的流动过程设备或AMT开发并转移到利兹的浆态反应器(WP4)中对这些进行测试。起始材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(WP5)，利兹公司产生的关于产品质量、成本和生产率的过程数据将用于与现有的手性胺制造劣质方法进行比较。制造同手性胺的方法是：(A)不对称还原胺化(如果需要，利兹的利物浦大学正在开发催化剂，可以进行放大)；(B)不对称转移氢化；(C)胺DKR通过固定化酶拆分、连续产物分离和CP-STAR催化的外消旋循环；(D)结晶诱导的不对称转化，包括手性胺结晶和母液的催化(E)氧化还原-中性胺烷基化反应，使用不对称借氢的不对称烷基胺。工业所需的手性胺是杂环的仲胺和叔胺，如哌啶、哌嗪、吡咯烷、吲哚等。在项目中，公司将提供每类手性胺的真实例子，以说明这项技术的潜力。流动方法的使用方便了多组分的筛选。将使用的流动反应器是固定床和滴流床、串联式CSTR和由AMT设计并转移到利兹进行评估的新型浆态反应器。这些反应堆都是中尺度的，这是产生适合放大生产的数据所必需的。这项工作的可测量输出是反选择性、转化率、产量、动力学和反应速率、质量平衡(即绿色指标，如工艺效率和浪费)、生产率、制造过程成本预测(原材料、运营和资本)。这些数据将与相同产品的现有工艺进行比较，以便进行成本效益分析，从而实现项目这一部分的主要目标。

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.