Improved Dehydration Process for Pharmaceutical Synthesis II

药物合成脱水工艺的改进 II

• 批准号: 8323263
• 负责人: Andrew Feiring
• 金额: $ 48.2万
• 依托单位: COMPACT MEMBRANE SYSTEMS, INC.
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8323263
• 关键词: Affect; Amination; Area; Automobile Driving; Biological Assay; Bromides; Chemicals; Chemistry; Commit; Consumption; Dehydration; Delaware; Development; Devices; Equilibrium; Evaluation; Excision; Feeds; Foxes; Heating; High temperature of physical object; Lead; Life; Membrane; Methods; NIH Program Announcements; Nature; Oxygen; Pharmacologic Substance; Phase; Physical condensation; Poison; Poisoning; Process; Production; Reaction; Reagent; Resistance; Savings; Sertraline; Side; Solvents; Suggestion; System; Technology; Temperature; Universities; Water; aprepitant; base; catalyst; celecoxib; cold temperature; cost; design; drug discovery; enzyme activity; improved; innovation; manufacturing process; molecular sieving; operation; planetary Atmosphere; professor; programs; reaction rate; research and development; sildenafil; success; tool; wasting; water environment

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.

描述（由申请人提供）：紧凑型膜系统（CMS）提议开发一种全氟膜反应堆技术，该技术将提供一种通常适用于从药物合成过程中去除水和氧气的工具。这项创新旨在提高产品质量并降低药品最终产品的制造成本。降低制造成本将来自提高的产品收益率，提高反应率和减少制造过程的能源输入要求。产品质量的改进将来自消除夹带物，共聚蒸馏和干燥试剂，以及在较低温度下运行并驱动反应物。该项目已扩展到包括去除氧气和水，以减少副反应和/或催化剂中毒，这在药物合成中应该广泛使用。该膜系统具有承受2200C的工艺温度，在几乎所有有机水环境中都具有普遍的适用性，以在诸如西地那非，塞勒克昔布，舍曲雷林和偶然的产品的合成中进行水分分离。鉴于可以达到较大的水有机化合物分离因子，膜的惰性以及承受严格的工作条件的能力，我们认为我们有一个理想的反应水和去除氧气的系统。提议者将开发膜系统和过程，而分包商将证明PD催化的胺化反应。在过去的十年中，这些反应彻底改变了药物发现和过程化学。 PD催化的胺化反应的效率可能会受到诸如水之类的杂质的负面影响。特拉华大学的FOX组，最近在CMS（和顾问）雇用了合成化学家（及其顾问）将证明膜过程在PD催化的胺化反应中的疗效，该研究将包括：合成芳基溴化物从Astra Zeneca Zeneca AR-A2过程中的合成；从AR-A2过程中合成PD催化的胺化产物；开发反应的GC分析；研究反应，无需去除水/氧气；并使用专有膜对芳基溴化物中间体干燥进行胺化研究。在第一阶段的成功中，许多工业合作伙伴已经在评估上花费了15万美元，或者致力于第二阶段的重大评估。