Javier Magano

Synthetic Approaches to the Neuraminidase Inhibitors Zanamivir (Relenza) and Oseltamivir Phosphate (Tamiflu) for the Treatment of Influenza

Influenza, a severe viral infection of the respiratory system, is responsible for a significant morbidity and mortality due to both annual epidemics and unpredictable pandemics. In the United States alone, 10-20% of the population is affected every year, which results in approximately 110,000 hospitalizations and more than 20,000 deaths with an estimated cost of U.S.

A SIMPLE AND EFFICIENT SYNTHESIS OF 2-(N-PHENYLAMINO)- BENZOIC ACIDS

12 billion.1 In addition to the annual occurrence of the disease, there is a growing concern that a worldwide pandemic will inevitably happen within the next few years. Since the 1500s, the world has seen 22 influenza pandemics, * Phone number: 1-(860)-6869021. Fax number: 1-(860)-7154978. E-mail address: Javier.Magano@Pfizer.com. Chem. Rev. XXXX, xxx, 000–000 A

Practical Synthesis of 1-(7-Fluoro-naphthalen-1-yl)piperazine Hydrochloride

ABSTRACT A new method for the synthesis of 2-(N-phenylamino)benzoic acids is presented, with 2-fluorobenzoic acids and anilines as starting materials. Several experimental conditions as well as the factors influencing the outcome of the reaction are described.

Synthesis of the Potassium Channel Opener (3S,4R)‐3,4‐Dihydro‐4‐(2,3‐dihydro‐2‐methyl‐3‐oxo‐pyridazin‐6‐Yl)oxy‐3‐hydroxy‐6‐(3‐hydroxyphenyl)sulphonyl‐2,2,3‐trimethyl‐2H‐benzo[b]pyran

Abstract A practical and scalable preparation of 1-(7-fluoronaphthalen-1-yl)-piperazine hydrochloride (1) is reported. The original route for the synthesis of this compound involved the use of 1-amino-7-fluoronaphthalene and bis(2-chloroethyl)amine hydrochloride, two highly toxic compounds. A new protocol has been developed that employs a palladium-catalyzed Buchwald–Hartwig cross-coupling reaction between 1-Boc-piperazine and 1-bromo-7-fluoronaphthalene followed by piperazine deprotection with HCl gas. In addition, an efficient palladium removal protocol allowed for the preparation of the target molecule with less than 20 ppm of this metal. This methodology has been successfully implemented to produce multigram quantities of 1 with excellent purity and low palladium content.

CHAPTER 15:Recent Large-Scale Applications of Transition Metal-Catalyzed Couplings for the Synthesis of Pharmaceuticals

Abstract The preparation of the potassium channel opener (3S,4R)‐3,4‐dihydro‐4‐(2,3‐dihydro‐2‐methyl‐3‐oxo‐pyridazin‐6‐yl)oxy‐3‐hydroxy‐6‐(3‐hydroxyphenyl)sulphonyl‐2,2,3‐trimethyl‐2H‐benzo[b]pyran (1) as a single enantiomer is reported. Considerable improvements have been implemented with respect to the original synthesis that allow for the preparation of multigram quantities of the final target compound. The optimized synthesis consists of a six‐step linear sequence whose key step is an asymmetric epoxidation protocol through the use of Jacobsens (S,S)‐(+)‐N,N′‐bis(3,5‐di‐tert‐butylsalicylidene)‐1,2‐cyclohexanediaminomanganese(III) chloride catalyst.

Large-Scale Applications of Transition Metal-Catalyzed Couplings for the Synthesis of Pharmaceuticals

A review on recent applications of transition metal-catalyzed couplings on a large scale (>100 mmol) in the pharmaceutical industry is presented. Carbon–carbon, carbon–nitrogen and carbon–sulfur bond formation are discussed and relevant examples of each type of coupling are described with synthetic schemes that show the cross-coupling step and also the structure of the final active pharmaceutical ingredient (API). Special emphasis is placed on the practical aspects of these chemistries to make them amenable for scale-up. In addition, important issues such as metal removal to comply with stringent regulatory specifications are discussed.