Large-Scale Synthesis of a Selective Inhibitor of the Norepinephrine Transporter: Mechanistic Aspects of Conversion of Indolinone Diol to Indolinone Aminoalcohol and Process Implications

Abstract

Development of a scalable synthesis of WAY-315193 is described. Use of LiHMDS as a base and Ti(O-i-Pr) 4 as a Lewis acid was optimal for efficient and reproducible addition of indolinone anion to epoxyalcohol. Conversion of indolinone diol to indolinone aminoalcohol was achieved via monotosylationmethylamination. The possibility of selective formation of the amidine side product, as well as its utilization for alternative selective preparation of the target aminoalcohol, was demonstrated.

Manipulating Activity and Chemoselectivity of a Benzaldehyde Lyase for Efficient Synthesis of α-Hydroxymethyl Ketones and One-Pot Enantio-Complementary Conversion to 1,2-Diols

“…Chiral 1,2-diols are important building blocks found in a diverse range of pharmaceutically important molecules and organic synthesis. − Enantioselective carbonyl reductases have been successfully used in the reduction of α-hydroxymethyl ketones to produce diols . In the previous study, especially the carbonyl reductase from Candida magnolia (CMCR), which belongs to the short-chain dehydrogenase family, was found to show excellent activity and stereoselectivity toward the reduction of α-hydroxy ketones .…”

A Practical Synthesis of 4’-Fluorospiro[cyclopropane-1,3’-indol]-2’(1’H)-one: a Valuable Terminal Building-Block for Biologically Active Podands

“…For example, a number of podands are recognized as highly active antibiotics. [2] On the other hand, a 4'-fluorospiro[cyclopropane-1,3'-indol]-2'(1'H)-one [3][4][5] scaffold and its bioisosteres [6] are important descriptors in different pharmacologically active agents, described as potential drugs for a variety of socially significant diseases. In such a case, we have made up our minds to prepare a series of podands, consisting of oligoether fragment, "locked" on both ends with the residues of 4'-fluorospiro[cyclopropane-1,3'-indol] ( Figure 1) and investigate their properties.…”

Development of a Pilot-Plant-Scale Synthesis of an Alkylated Dihydrobenzothiadiazole S,S-Dioxide: Incorporation of a Late-Stage Mitsunobu Reaction

“…The synthesis of monoamine reuptake inhibitors was an area of focused research within Wyeth. − These compounds have shown potential in the treatment and prevention of a variety of conditions and disorders that includes, but is not limited to, vasomotor symptoms (e.g., hot flashes), depressive disorders, and some pain conditions such as diabetic neuropathy and fibromyalgia. Aryl sulfamide derivatives have been particularly attractive targets, and compound 11 advanced recently along with requests to deliver multikilogram quantities.…”