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Manufacture of chiral amines using catalytic and flow processing methods

使用催化和流动加工方法制造手性胺

基本信息

批准号：
EP/K504154/1
负责人：
Andrew Blacker
金额：
$ 23.06万
依托单位：
University of Leeds
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2013
资助国家：
英国
起止时间：
2013 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=EP%2FK504154%2F1
关键词：
Manufacture chiral amines using catalytic

项目摘要

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.

手性胺是40%的医药产品和20%的作物保护化合物中使用的重要组成部分，是高价值的化学中间体。然而，目前的制造方法效率低下，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好的方法来制造仲环和杂环手性胺。通常的工艺采用对映体分辨率（最大收率50%），这增加了处理步骤和成本。事实上，ASC制药圆桌会议已将这类反应列为最需要解决的问题之一，并将连续加工列为重点绿色工程研究领域的头号目标。Blacker和Xiao用间歇法研究并发表了手性胺工艺，但没有采用流动法。催化剂的分离及其在工艺中的成本阻碍了工业采用。在目前的项目中，这些问题将在流动中使用Cp-star催化剂。利兹团队负责测试，工艺开发和扩大/扩大多达5种不同的工艺，以制造同手性仲杂环胺或叔杂环胺（WP2）。这些研究需要在利物浦（WP1）和YPT （WP3）生产的固体支撑催化剂（Cp-Star）和配体，利兹大学将在iPRD工艺实验室已经拥有的流动工艺设备上进行测试，或者在AMT （WP4）开发并转移到利兹大学的泥浆反应器上进行测试。起始材料和分析方法将由合作的最终用户公司（阿斯利康、辉瑞、先正达和redys博士）提供（WP5），利兹产生的关于产品质量、成本和生产率的工艺数据将用于与现有的较差的手性胺制造方法进行比较。制造同手性胺的工艺有：(a)不对称还原胺化（催化剂正在利物浦开发，利兹可以根据需要进行放大）；(b)不对称转移加氢；(c)通过固定化酶分解、连续产物分离和cp星催化外消旋再循环的胺DKR (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)利用借氢对映选择性烷基化胺的氧化还原-中性胺烷基化。工业上需要的手性胺是杂环仲、叔胺，如哌啶、哌嗪、吡啶、吲哚等。在该项目中，两家公司将提供每一类手性胺的真实样品，以说明这项技术的潜力。流动方法的使用有利于多种化合物的筛选。将使用的流动反应器是固定床和滴流床、梯级CSTR和AMT正在设计的新型浆液反应器，并将在这些系统中进行评估。反应器都是中尺度的，这是产生适合规模化生产的数据所必需的。工作的可测量输出是对映选择性、转化率、产率、动力学和反应速率、质量平衡（即绿色指标，如过程效率和浪费）、生产率、制造过程成本预测（原材料、操作和资本）。这些数据将与相同产品的现有流程进行比较，以实现成本效益分析，从而实现这部分项目的主要目标。