The compound (+)-2-(7-chloro-1,8-naphthyridin-2-yl)-3S-(5methyl-2-oxohexyl)-1-isoindolinone (pagoclone) shows anxiolytic activity due to partial agonism of the benzodiazepine site of the GABA A receptor. We describe the development of an economical and practical process for a 100+ kg pilot plant production used to supply development needs. For the key reaction, a β-keto phosphonium salt was prepared by selectively reacting a primary r-bromo ketone with triphenylphosphine in the presence of a secondary r-bromo ketone. A novel Wittig reaction with a 1-isoindolinone was used to produce racemic pagoclone. The enantiomerically pure drug substance was prepared by hydrolyzing a γ-lactam and resolving the resulting enantiomeric carboxylic acids with (+)-ephedrine hemihydrate. An alternate resolution, involving chiral multicolumn chromatography (MCC) was also developed. The synthesis was completed by a racemization-free lactam formation to afford pagoclone.
This paper describes a method for automatically inspecting the top edge region of a wafer for defects and how this method was used to evaluate process improvements. The need for such an inspection was driven by a within wafer defect problem first seen on product. The root cause of the defect was found to be the redistribution of certain defect types from the wafer edge exclusion region into the product area. Process partition and manual inspection using a scanning electron microscope (SEM) revealed the mechanism to be the formation and rupture of blisters during part of the process sequence. These blisters were found to be as small as 2µm, and appeared along the top edge of wafers. During processing, a high percentage of these blisters would rupture and redeposit debris on the topside of the wafer resulting in nearly 100 percent kill rate. While the root cause was understood, the use of SEM inspection to quantifiably evaluate process improvements intended to reduce the edge defects was impractical. This was deemed impractical because of the large of the number of wafers required to generate meaningful statistics and the number of process options. Additionally, manual inspections used to count the number of defects were inconsistent as well as slow. An automated macro defect inspection system (August Technology AXi™ Series 930) was used in a novel way to enable fast, accurate, and repeatable defect counts from the wafer top edge to help determine the most appropriate process improvement.
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