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The development of multikilogram scale green and economical synthetic route of enantiomerically pure cis-4-amino-3-fluoro-1-methylpiperidine 1 is described. The synthesis features a highly regio-, ...

An efficient general methodology for the synthesis of 4-quinolinyl ethers is demonstrated via a highly reactive SNAr reaction of 4-quinolinyl sulfones with a range of structurally diversified 1°, 2°, and 3° alcohols with a wide substrate scope and high yields. By adapting this methodology, a convergent synthesis of a complex target of HCV NS3/4a protease inhibitor BI 201420 was accomplished.

Firocoxib (ML-1,785,713) is a nonsteroidal, potent, and selective COX-2 inhibitor, approved for the control of pain and inflammation associated with osteoarthritis in dogs and horses, as well as to control postoperative pain and inflammation in dogs. We employed a six-step synthesis to prepare firocoxib-[13 C6 ] in an overall yield of 35% from the commercially available bromobenzene-[13 C6 ]. The synthetic route involved the preparation of the key intermediate phenyl-13 C6 -methyl sulfide using cesium carbonate and S-methylthiourea sulfate under transition-metal free conditions. A two-step preparation of firocoxib-[13 C,2 H3 ] via the sulfinic acid derivative of firocoxib and methyl iodide-[13 C,2 H3 ] using the procedure of Gauthier and Yoshikawa was first undertaken. However, the deuterium atoms of the methyl sulfone undergo extensive exchange in aqueous media even at neutral pH. The isotope-labelled firocoxib is intended as an internal standard for bioanalyses of firocoxib from biological matrices.

An efficient general methodology for the synthesis of 4-quinolinyl ethers is demonstrated via a highly reactive S

Metal-catalyzed cross-coupling reactions are extensively employed in both academia and industry for the synthesis of biaryl derivatives for applications to both medicine and material science. Application of these methods to prepare tetra-ortho-substituted biaryls leads to chiral atropisomeric products that introduces the opportunity to use catalyst-control to develop asymmetric cross-coupling procedures to access these important compounds. Asymmetric Pd-catalyzed Suzuki-Miyaura and Negishi cross-coupling reactions to form tetra-ortho-substituted biaryls were studied employing a collection of P-chiral dihydrobenzooxaphosphole (BOP) and dihydrobenzoazaphosphole (BAP) ligands. Enantioselectivities of up to 95:5 and 85:15 er were identified for the Suzuki-Miyaura and Negishi cross-coupling reactions, respectively. Unique ligands for the Suzuki-Miyaura reaction vs the Negishi reaction were identified. A computational study on these Suzuki-Miyaura and Negishi cross-coupling reactions enabled an understanding in the differences between the enantiodiscriminating events between these two cross-coupling reactions. These results support that enantioselectivity in the Negishi reaction results from the reductive elimination step, whereas all steps in the Suzuki-Miyaura catalytic cycle contribute to the overall enantioselection with transmetalation and reductive elimination providing the most contribution to the observed selectivities.

A chromatography-free, asymmetric synthesis of the C2-symmetric P-chiral diphosphine t-Bu-SMS-Phos was developed using a chiral auxiliary-based approach in five steps from the chiral auxiliary in 36% overall yield. Separtion and recovery of the auxiliary were achieved with good yield (97%) to enable recycling of the chiral auxiliary. An air-stable crystalline form of the final ligand was identified to enable isolation of the final ligand by crystallization to avoid chromatography. This synthetic route was applied to prepare up to 4 kg of the final ligand. The utility of this material was demonstrated in the asymmetric hydrogenation of trifluoromethyl vinyl acetate at 0.1 mol % Rh loading to access a surrogate for the pharmaceutically relavent chiral trifluoroisopropanol fragment in excellent yield and enantiomeric excess (98.6%).

Metal-catalyzed cross-coupling reactions are extensively employed in both academia and industry for the synthesis of biaryl derivatives for applications to both medicine and material science. Application of these methods to prepare tetra-ortho-substituted biaryls leads to chiral atropisomeric products that introduces the opportunity to use catalyst-control to develop asymmetric cross-coupling procedures to access these important compounds. Asymmetric Pd-catalyzed Suzuki-Miyaura and Negishi cross-coupling reactions to form tetra-ortho-substituted biaryls were studied employing a collection of P-chiral dihydrobenzooxaphosphole (BOP) and dihydrobenzoazaphosphole (BAP) ligands. Enantioselectivities of up to 95:5 and 85:15 er were identified for the Suzuki-Miyaura and Negishi cross-coupling reactions, respectively. Unique ligands for the Suzuki-Miyaura reaction vs the Negishi reaction were identified. A computational study on these Suzuki-Miyaura and Negishi cross-coupling reactions enabled an understanding in the differences between the enantiodiscriminating events between these two cross-coupling reactions. These results support that enantioselectivity in the Negishi reaction results from the reductive elimination step, whereas all steps in the Suzuki-Miyaura catalytic cycle contribute to the overall enantioselection with transmetalation and reductive elimination providing the most contribution to the observed selectivities.

Vitamin E-TPGS (d-α-tocopheryl polyethylene glycol succinate) is a common excipient used in drug formulations. This excipient is formed by esterification of Vitamin E succinate with polyethylene glycol. As part of an oral formulation for active pharmaceutical ingredient (API) Faldaprevir, Vitamin E-TPGS was found to decompose under ambient conditions producing free (±)-α-Tocopherol which subsequently formed an adduct composed of α-Tocopherol and the API. The addition product was isolated using liquid chromatography with collections onto solid-phase extraction cartridges, and full structure elucidation was achieved using mass spectrometry and nuclear magnetic resonance spectroscopy. The results revealed a regioselective addition of α-Tocopherol to the API that likely occurs through the formation of a stabilized ortho-quinone methide intermediate. This finding demonstrates the propensity of the common excipient (Vitamin E-TPGS) to generate chemically active intermediates that may react with formulation ingredients.

Enantioselective synthesis of α-aryl and α-heteroaryl piperidines is reported. The key step is an iridium-catalyzed asymmetric hydrogenation of substituted N-benzyl pyridinium salts. High levels of enantioselectivity up to 99.3:0.7 er were obtained for a range of α-heteroaryl piperidines. DFT calculations support an outer-sphere dissociative mechanism for the pyridinium reduction. Notably, initial protonation of the final enamine intermediate determines the stereochemical outcome of the transformation rather than hydride reduction of the resultant iminium intermediate.

A chromatography-free, asymmetric synthesis of the C2-symmetric P-chiral diphosphine t-Bu-SMS-Phos was developed using a chiral auxiliary-based approach in five steps from the chiral auxiliary in 36% overall yield. Separtion and recovery of the auxiliary were achieved with good yield (97%) to enable recycling of the chiral auxiliary. An air-stable crystalline form of the final ligand was identified to enable isolation of the final ligand by crystallization to avoid chromatography. This synthetic route was applied to prepare up to 4 kg of the final ligand. The utility of this material was demonstrated in the asymmetric hydrogenation of trifluoromethyl vinyl acetate at 0.1 mol % Rh loading to access a surrogate for the pharmaceutically relavent chiral trifluoroisopropanol fragment in excellent yield and enantiomeric excess (98.6%).

Air-stable P-chiral dihydrobenzooxaphosphole oxazoline ligands were designed and synthesized. When they were used in the iridium-catalyzed asymmetric hydrogenation of unfunctionalized 1-aryl-3,4-dihydronaphthalenes under one atmosphere pressure of H2 , up to 99:1 e.r. was obtained. High enantioselectivities were also observed in the reduction of the exocyclic imine derivatives of 1-tetralones.

The structural analysis (i.e., identification) of organic chemical entities leached into drug product formulations has traditionally been accomplished with techniques involving the combination of chromatography with mass spectrometry. These include gas chromatography/mass spectrometry (GC/MS) for volatile and semi-volatile compounds, and various forms of liquid chromatography/mass spectrometry (LC/MS or HPLC/MS) for semi-volatile and relatively non-volatile compounds. GC/MS and LC/MS techniques are complementary for structural analysis of leachables and potentially leachable organic compounds produced via laboratory extraction of pharmaceutical container closure/delivery system components and corresponding materials of construction. Both hyphenated analytical techniques possess the separating capability, compound specific detection attributes, and sensitivity required to effectively analyze complex mixtures of trace level organic compounds. However, hyphenated techniques based on mass spectrometry are limited by the inability to determine complete bond connectivity, the inability to distinguish between many types of structural isomers, and the inability to unambiguously determine aromatic substitution patterns. Nuclear magnetic resonance spectroscopy (NMR) does not have these limitations; hence it can serve as a complement to mass spectrometry. However, NMR technology is inherently insensitive and its ability to interface with chromatography has been historically challenging. This article describes the application of NMR coupled with liquid chromatography and automated solid phase extraction (SPE-LC/NMR) to the structural analysis of extractable organic compounds from a pharmaceutical packaging material of construction. The SPE-LC/NMR technology combined with micro-cryoprobe technology afforded the sensitivity and sample mass required for full structure elucidation. Optimization of the SPE-LC/NMR analytical method was achieved using a series of model compounds representing the chemical diversity of extractables. This study demonstrates the complementary nature of SPE-LC/NMR with LC/MS for this particular pharmaceutical application. LAY ABSTRACT: The identification of impurities leached into drugs from the components and materials associated with pharmaceutical containers, packaging components, and materials has historically been done using laboratory techniques based on the combination of chromatography with mass spectrometry. Such analytical techniques are widely recognized as having the selectivity and sensitivity required to separate the complex mixtures of impurities often encountered in such identification studies, including both the identification of leachable impurities as well as potential leachable impurities produced by laboratory extraction of packaging components and materials. However, while mass spectrometry–based analytical techniques have limitations for this application, newer analytical techniques based on the combination of chromatography with nuclear magnetic resonance spectroscopy provide an added dimension of structural definition. This article describes the development, optimization, and application of an analytical technique based on the combination of chromatography and nuclear magnetic resonance spectroscopy to the identification of potential leachable impurities from a pharmaceutical packaging material. The complementary nature of the analytical techniques for this particular pharmaceutical application is demonstrated.

The term “leachables” refers to impurities in pharmaceutical products whose origin is the pharmaceutical container closure system in either direct or indirect contact with the formulation. Potentia...

In this work we report the identification of unknown degradation products observed during the accelerated stability studies of a Hepatitis C Virus inhibitor drug product by using LC/MS and forced degradation studies. These degradation products are formed through chemical interaction between the Active Pharmaceutical Ingredient (API) and meglumine, an excipient in the drug formulation.

Acknowledgements. Dedication. Preface. Part I. Development of Safety Thresholds, Safety Evaluation, and Qualification of Extractables and Leachable in Orally Inhaled Nasal Drug Products. 1. Chapter 1. Overview of Leachables and Extractables in Orally Inhaled and Nasal Products (Douglas J. Ball, Daniel L. Norwood, Lee M. Nagao). 2. Chapter 2. A General Overview of the Suitability for Intended Use Requirements for Materials Used in Pharmaceutical Systems (Dennis Jenke). 3. Chapter 3. Concepts and Application of Safety Thresholds in Drug Development (David Jacobson-Kram and Ronald D. Snyder). 4. Chapter 4. The Development of Safety Thresholds for Leachables on Orally Inhaled and Nasal Drug Products (W. Mark Vogel). 5. Chapter 5. The Analytical Evaluation Thresholds (AET) and its Relationship to Safety Thresholds (Daniel L. Norwood, James O. Mullis, Scott Pennino). 6. Chapter 6. Safety Thresholds in the Pharmaceutical Development Process for OINDP: An Industry Perspective (David Alexander and James Blanchard). 7. Chapter 7. The Chemistry and Toxicology Partnership: Extractables and Leachables Information Sharing Among the Chemists and Toxicologists (Cheryl L. M. Stults, Ronald Wolff, Douglas J. Ball). 8. Chapter 8. Use of Safety Thresolds in the Pharmaceutical Development Process for OINDP: US Regulatory Perspectives (Timothy J. McGovern). 9. Chapter 9. The Application of Safety Thresholds to Quality Leachables from Plastic Container Closure Systems Intended for Pharmaceutical Products: A Regulatory Perspective (Kumudini Nicholas). Part 2. Best Practices for Evaluation and Management of Extractables and Leachables in Orally Inhaled and Nasal Drug Products. 10. Chapter 10. Analytical Best Practices for the Evaluation and Management of Extractables and Leachables in Orally Inhaled and Nasal Drug Products (Dan Norwood, Cheryl Stults and Lee Nagao). 11. Chapter 11. Chemical and Physical Attributes of Plastics and Elastomers: Impact on the Extractables Profile of Container Closure Systems (Michael A Ruberto and Diane Paskiet). 12. Chapter 12. Pharmaceutical Container Closure System Selection & Qualification of Materials (Douglas J. Ball, William P. Beierschmitt, and Arthur J. Shaw). 13. Chapter 13. Analytical Techniques for Identification of Extractables and Leachables (Dan Norwood, Thomas N. Feinberg, James O. Mullis, and Scott Pennino). 14. Chapter 14. Extractables The Controlled Extraction Study (Thomas N. Feinberg, Daniel L. Norwood, Alice T. Granger, and Dennis Jenke). 15. Chapter 15. Extractables Case Study of a Sulfur Elastomer (Daniel L. Norwood, Fenghe Qiu, James Coleman, James O. Mullis, Alice T. Granger, Keith McKellop, Michelle Raikes, John Robson, David Olenski, John Hand, Sr., Melinda K. Munos, Tianjing Deng, Xiaochun Yu, Derek Wood, Shauang Li, Song Klapoetke and Xiaoya Ding). 16. Chapter 16. Extractables Case Study of a Polypropylene (Diane Paskiet, Laura Stubbs, and Alan D. Hendricker). 17. Chapter 17. Leachables Analytical Leachables Studies (Andrew D. Feilden and Andy Rignall). 18. Chapter 18. Development and Optimization of Methods for Routine Testing (Cheryl L. Stults and Jason M. Creasey). 19. Chapter 19. Critical Component Quality Control and Specification Strategies (Terrence Tougas, Suzette Roan, and Barbara Falco). 20. Chapter 20. Inorganic Leachables (Diane Paskiet, Ernest L. Lippert, Brian D. Mitchell, and Diego Zurbriggen). 21. Chapter 21. Foreign Particulate Matter (James Coleman, John A. Robson, John A. Smoliga, and Cornelia B. Field).

Impurities in pharmaceutical products do not enhance the desired therapeutic effect and may, of course, have adverse effects. Impurities must therefore be limited or controlled for quality and safety considerations. Structural identification of an impurity is the first step in understanding the chemistry of its formation and subsequently controlling the impurity. In this article, the chemical structure of an unknown by-product formed during the synthesis of a nevirapine analogue HIV NNRT inhibitor was identified using a combination of low resolution, high resolution and H/D exchange LC/MS and LC/MS/MS. The origin of the impurity was investigated through a series of photo- and oxidative stress studies. It was concluded that this impurity is formed via a side-reaction of the last intermediate with the oxidant used in the synthesis.

SMP is producing spherical, micron-sized, controlled size distribution powders that can be deposited by conventional and advanced deposition techniques to produce densely packed powder layers. This presentation focuses on the production, deposition methods, characteristics and performance of these phosphor powders used in miniature CRT displays.