Compounds Currently in Phase II−III Clinical Trials of Major Pharmaceutical Companies: New Structural Trends and Therapeutic Areas Yu Zhou,† Jiang Wang,† Zhanni Gu,† Shuni Wang,† Wei Zhu,† Jose ́ Luis Aceña,*,‡,§ Vadim A. Soloshonok,*,‡,∥ Kunisuke Izawa,* and Hong Liu*,† †Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China ‡Department of Organic Chemistry I, Faculty of Chemistry, University of the Basque Country UPV/EHU, Paseo Manuel Lardizab́al 3, 20018 San Sebastiań, Spain Department of Organic Chemistry, Autońoma University of Madrid, Cantoblanco, 28049 Madrid, Spain IKERBASQUE, Basque Foundation for Science, María Díaz de Haro 3, 48013 Bilbao, Spain Hamari Chemicals Ltd., 1-4-29 Kunijima, Higashi-Yodogawa-ku, Osaka, Japan 533-0024

Next Generation of Fluorine-Containing Pharmaceuticals, Compounds Currently in Phase II–III Clinical Trials of Major Pharmaceutical Companies: New Structural Trends and Therapeutic Areas

The Golden Age of Transfer Hydrogenation

The electronic properties and relatively small size of fluorine endow it with considerable versatility as a bioisostere and it has found application as a substitute for lone pairs of electrons, the hydrogen atom, and the methyl group while also acting as a functional mimetic of the carbonyl, carbinol, and nitrile moieties. In this context, fluorine substitution can influence the potency, conformation, metabolism, membrane permeability, and P-gp recognition of a molecule and temper inhibition of the hERG channel by basic amines. However, as a consequence of the unique properties of fluorine, it features prominently in the design of higher order structural metaphors that are more esoteric in their conception and which reflect a more sophisticated molecular construction that broadens biological mimesis. In this Perspective, applications of fluorine in the construction of bioisosteric elements designed to enhance the in vitro and in vivo properties of a molecule are summarized.

Fluorine and Fluorinated Motifs in the Design and Application of Bioisosteres for Drug Design.

Palladium-catalyzed carbonylation reactions of aromatic halides in the presence of various nucleophiles have undergone rapid development since the pioneering work of Heck and co-workers in 1974, such that nowadays a plethora of palladium catalysts are available for different carbonylative transformations. The carboxylic acid derivatives, aldehydes, and ketones prepared in this way are important intermediates in the manufacture of dyes, pharmaceuticals, agrochemicals, and other industrial products. In this Review, the recent academic developments in this area and the first industrial processes are summarized.

Palladium-catalyzed carbonylation reactions of aryl halides and related compounds.

The last 15 years of hydroformylation and carbonylation chemistry are reviewed, including technical and commercial aspects.

Progress in hydroformylation and carbonylation

A process for producing an N-carbamate-protected 3-amino-1,2-epoxy-4-(hydroxyphenyl)butane with a high optical purity in a high yield, which comprises hydrogenating an N-carbamate-protected 3-amino-1-chloro-2-hydroxy-4-(benzyloxyphenyl)butane in the presence of a metal catalyst to obtain an N-carbamate-protected 3-amino-1-chloro-2-hydroxy-4-(hydroxyphenyl)butane and treating the hydrogenation product with a base.

Process for producing aminoepoxide

A process for purifying N-protected-s-amino alcohols (such as (2R, 3S)- or (2S, 3R)-3-t-butoxycarbonylamino-1 halo -2-hydroxy-4-phenylbutane) either by adding water to a solution of such an alcohol in a polar organic solvent to crystallize the alcohol or by crystallizing such an alcohol from a diol or a diol-base mixed solvent; and a process of subjecting an N-protected-s-amino alcohol thus purified to treatment with a base to obtain the corresponding N-protected-s-amino epoxide. N-Protected-s-amino alcohols and N-protected-s-amino epoxides are useful as intermediates in the synthesis of HIV protease inhibitors and other drugs.

Processes for preparation of n-protected-beta-amino alcohols and n-protected-beta-amino epoxides

Two industrial synthetic approaches to Lodenosine (1, FddA, 9-(2,3-dideoxy- 2-fluoro-β-D-threo-pentofuranosyl) adenine) via a purine riboside or a purine 3′-deoxyriboside are described. Several novel applications of deoxygenation and fluorination methods are compared considering reaction yields, economy, safety and environmental concerns.

An Industrial Process for Synthesizing Lodenosine (FddA)

The present invention provides a method for industrially producing an optically active lysine derivative useful as a pharmaceutical intermediate. More particularly, the present invention provides a production method including protecting an amino group or an amino group and carboxyl group of optically active 2-amino-6-methyl-6-nitroheptanoic acid with a protecting group, reducing a nitro group to synthesize a 6,6-dimethyl lysine derivative and reacting the 6,6-dimethyl lysine derivative with an acetic acid derivative.

Method for producing lysine derivative

A facile method for the synthesis of 3′-α-fluoro-2′,3′-dideoxyadenosine 6 has been developed. Fluorination of 5′- O -acetyl-3′-β-bromo-3′-deoxyadenosine 3 with MOST gave 2′-β-bromo-3′-α-fluoro-2′,3′-dideoxyadenosine 4 via a rearrangement of the 3′-β-bromine to the 2′-β position during 3′-α fluorination. The 2′-β bromine was reduced by radical reduction and then the 5′- O -acetyl group was removed to afford 3′-α-fluoro-2′,3′-dideoxyadenosine 6 in good yield. A possible mechanism for the rearrangement is discussed.

Kunisuke Izawa

Papers

Process for producing aminoepoxide

Processes for preparation of n-protected-beta-amino alcohols and n-protected-beta-amino epoxides

An Industrial Process for Synthesizing Lodenosine (FddA)

Method for producing lysine derivative

A Synthesis of 3′-α-Fluoro-2′,3′-dideoxyadenosine via a Bromine Rearrangement During Fluorination with MOST Reagent.