A Robust and Scalable Process for the Synthesis of Substantially Pure Clarithromycin 9-(E)-Oxime with an Established Control of the (Z)-Isomer Impurity.

Controlling the isomeric impurity in a key raw material is always critical to achieve the corresponding pure isomer-free targeted active pharmaceutical ingredient (API) in downstream processing. Clarithromycin 9-(E)-oxime is the key raw material for the synthesis of the 9a-lactam macrolide, which is an interesting scaffold for the synthesis of several bioactive macrolides. Here demonstrated is a scalable process for the preparation of substantially pure clarithromycin 9-(E)-oxime, with less than 1.2% of the (Z)-isomer. The process does not involve a separate time-consuming purification by a crystallization operation to purge the undesired (Z)-oxime isomer. Further, the pure clarithromycin 9-(E)-oxime obtained was subjected to the Beckmann rearrangement, thereby converting it into the pure 9a-lactam scaffold. Additionally, a few other impurities were identified and controlled at each stage. The fine-tuned process was successfully up scaled to a multikilogram scale, enabling the large-scale manufacturing of potential APIs derived from this scaffold.

Synthesis of analogs of forodesine HCl, a human purine nucleoside phosphorylase inhibitor-Part I.

Forodesine HCl is being investigated as a potential therapeutic target for the control of T-cell proliferation. During our ongoing process development work on forodesine HCl several novel compounds were identified as possible impurities in the process. Herein we present the synthesis of three novel compounds (2-4).

Syntheses of novel high affinity ligands for opioid receptors.

A series of novel high affinity opioid receptor ligands have been made whereby the phenolic-OH group of nalbuphine, naltrexone methiodide, 6-desoxonaltrexone, hydromorphone and naltrindole was replaced by a carboxamido group and the furan ring was opened to the corresponding 4-OH derivatives. These furan ring 'open' derivatives display very high affinity for mu and kappa receptors and much less affinity for delta. The observation that these target compounds have much higher receptor affinity than the corresponding ring 'closed' carboxamides significantly strengthens our underlying pharmacophore hypothesis concerning the bioactive conformation of the carboxamide group.

Redefining the structure-activity relationships of 2,6-methano-3-benzazocines. Part 7: syntheses and opioid receptor properties of cyclic variants of cyclazocine.

A series of 7,8- and 8,9-fused triazole and imidazole analogues of cyclazocine have been made and characterized in opioid receptor binding and [(35)S]GTPgammaS assays. Target compounds were designed to explore the SAR surrounding our lead molecule for this study, namely the 8,9-fused pyrrolo analogue 2 of cyclazocine. Compared to 2, many of the new compounds in this study displayed very high affinity for opioid receptors.

Synthesis of conformationally constrained lysine analogues.

The synthesis of two conformationally constrained lysine analogues is reported. The synthesis of the novel analogue 1 based on the 3-aza-bicyclo[3.1.0]hexane system is accomplished from the known tricycle 3 in eight steps. The synthesis of the analogue 2 is accomplished in eight steps from 4-hydroxy proline. Both analogues are synthesized appropriately protected for Fmoc/Boc solid-phase peptide synthesis.