Microwave Assisted Partial Synthesis of Enantiomerically Pure S-ispinesib-A case study

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Date: June 30, 2013
Publisher: Knowledge Bylanes
Document Type: Report
Length: 1,741 words
Lexile Measure: 1470L

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Byline: UMER RASHID, AHSANULLAH, MUHAMMAD WASEEM AND FARZANA LATIF ANSARI

Summary: Ispinesib, a quinazolinone derivative, is the first candidate that has entered clinical trials aimed at developing novel KSP inhibitors. It was discovered by Cytokinetics in a high-throughput screening effort followed by lead optimization of the identified KSP inhibitors. The synthetic route, which involved eleven steps, was problematic with an overall yield of only about 8%. Later a new synthetic strategy was developed which involved the introduction of the chiral center in the very first step using an enantiomerically pure amino acid which led to the synthesis of enantiomerically pure quinazolinones nucleus. Following this route, the yield rose to about 40 % together with a reduction in the manufacturing cost. Present study is the first ever reinvestigation of the partial synthesis of enantiomerically pure ispinesib under microwave irradiation by optimizing the reaction conditions for two bottleneck steps of the synthesis of ispinesib via two routes.

The aim of study was to reduce the reaction time and the number of steps and then scale-up the microwave synthesis to synthesize multigrams of ispinesib by using continuous flow processing approach. Route 1 involves the synthesis of quinazolinone core under MW irradiation in a one-pot, two-step reaction sequence using D-valine while Route 2 takes into account N-alkylation of D-valine methyl ester via reductive amination prior to the formation of quinazolinone nucleus.

Keywords: Ispinesib, KSP inhibitors, amino acid, microwave.

Introduction

Kinesin spindle protein, (also called KSP or kinesin-5) has emerged as a promising target for a new generation antimitotic chemotherapeutic agents[1]. The discovery of monastrol, which was the first small, specific and cell permeable KSP inhibitor, led to several other small molecules as KSP inhibitors [2-13]. Ispinesib (SB715992), having a quinazolinone core is an experimental KSP inhibitor from Cytokinetics and GlaxoSmithKline, has emerged as a potent KSP inhibitor with subnanomolar Ki that has already entered clinical trials [14-16].

In medicinal chemistry 2,3-disubstituted 3H- quinazolin-4-one moiety 1 is a widely researched scaffold and is present in many biologically active compounds such as methaqualone, chloroqualone, and piriqualone [17-19]. Moreover, quinazolinone core containing drugs are among a growing number of therapeutic agents with antiproliferative activity [20-22].

In a high-throughput screening effort, Cytokinetics discovered ispinesib as a strong KSP inhibitor. The synthetic route involved eleven steps with 8% overall yield [14]. The major difficulties encountered were very long reaction time, use of undesirable reagents, reliance on chiral resolution and problems related to its commercial-scale manufacturing. The general strategy for its complete synthesis is shown in Scheme-1[23].

It may be seen from scheme-1 that step 5 developed in an attempt to avoid the chromatographic resolution,...

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Gale Document Number: GALE|A335710169