Improved Dehydration Process for Pharmaceutical Synthesis II

描述(由申请人提供)：紧凑型膜系统公司(CMS)建议开发一种全氟膜反应器技术，该技术将为从药物合成过程中去除水和氧气提供一种普遍适用的工具。这一创新旨在提高产品质量，降低医药终端产品的制造成本。制造成本的降低将源于产品产量的提高、反应速度的提高和制造过程中能源投入的减少。通过消除过程中的夹带剂、共沸蒸馏和干燥试剂，以及在较低温度下操作和驱动反应物，可以提高产品质量。该项目已扩大到包括氧气和水的去除，以努力减少副反应和/或催化剂中毒，这在药物合成中应该得到广泛使用。这种膜系统能够承受2200℃的工艺温度，使其在几乎任何有机水环境中都具有普遍的适用性，可用于合成西地那非、塞来昔布、舍曲林和异丙肾上腺素等产品的水分离。考虑到可以实现的较大的水-有机化合物分离系数、膜的惰性以及承受恶劣操作条件的能力，我们相信我们拥有一个理想的反应除水和除氧系统。建议书将开发膜系统和工艺，而分包商将演示钯催化的胺化反应。在过去的十年里，这些反应给药物发现和过程化学带来了革命性的变化。钯催化的胺化反应的效率会受到水等杂质的负面影响。特拉华大学的Fox小组和CMS最近聘请的合成化学家(以及顾问)将在一项研究中展示膜过程在Pd催化的胺化反应中的功效，该研究将包括：由Astra Zeneca AR-A2过程合成芳基溴中间体；从AR-A2过程合成Pd催化的胺化产品；为这些反应开发GC分析方法；研究不除水/除氧的控制反应；以及使用专有膜研究芳香溴中间体的干燥。随着第一阶段的成功，许多行业合作伙伴要么已经在评估上花费了超过15万美元，要么承诺在第二阶段进行重大评估。

DESCRIPTION (provided by applicant): Compact Membrane Systems (CMS) proposes to develop a perfluoro membrane reactor technology that will provide a generally applicable tool for removing water and oxygen from pharmaceutical synthesis processes. This innovation aims to improve product quality and reduce manufacturing costs of pharmaceutical end products. Manufacturing cost reductions will be derived from improved product yields, increased reaction rates and reduced energy input requirements of the manufacturing process. Product quality improvements will be derived from the elimination of entrainers, azeotropic distillation, and drying reagents in the process as well as operation at lower temperatures and driving the reactant. The project has been expanded to include the removal of both oxygen and water in an effort to reduce side reactions and/or catalyst poisoning which should be of broad use in pharmaceutical synthesis. This membrane system has the capability to withstand process temperatures of 2200C endowing it with universal applicability in almost any organic-water environment for water separation in the synthesis of products such as sildenafil, celecoxib, sertraline, and aprepitant. Given the large water-organic compound separation factors achievable, the inertness of the membrane, and the ability to withstand harsh operating conditions, we believe we have an ideal system for reaction water and oxygen removal. The proposer will develop the membrane system and processes while the subcontractors will demonstrate Pd-catalyzed amination reactions. These reactions have revolutionized drug discovery and process chemistry in the past decade. The efficiency of Pd-catalyzed amination reactions can be negatively affected by impurities such as water. The Fox group at the University of Delaware and recently hired synthesis chemists at CMS (and consultants) will demonstrate the efficacy of the membrane process in Pd-catalyzed amination reactions in a study that will consist of: synthesis of the aryl bromide intermediate from the Astra Zeneca AR-A2 process; synthesis of the Pd-catalyzed amination product from the AR-A2 process; development of GC assays for the reactions; study of a control reaction without water/oxygen removal; and, study of amination with drying of the aryl bromide intermediate using the proprietary membrane. With success in Phase I, numerous industrial partners have either already spent over $150,000 on evaluation or committed to major evaluations in Phase II.