Kirtee Wani, Shyamapada Banerjee, Nipun Davar and Yogesh S. Sanghvi*,
{"title":"Development of a Kilogram-Scale Manufacturing Route for Bis-Tac-dG: Essential Building-Block for Guadecitabine","authors":"Kirtee Wani, Shyamapada Banerjee, Nipun Davar and Yogesh S. Sanghvi*, ","doi":"10.1021/acs.oprd.4c00073","DOIUrl":null,"url":null,"abstract":"<p >Guadecitabine (SGI-110) is a dinucleotide that is a prodrug of decitabine. The dinucleotide contains decitabine (top fragment) and 2′-deoxyguanosine (<b>9</b>; dG; bottom fragment) connected via a 3′ → 5′ phosphodiester bond. The manufacturing process of guadecitabine requires a large quantity of <i>N</i><sup>2</sup>, 3′-<i>O</i>-(4-<i>tert</i>-butylphenoxyacetyl)-protected dG (<b>2</b>; Bis-Tac-dG) to incorporate the bottom fragment. The protected <b>2</b> being a critical starting material of the dinucleotide imposes stringent quality requirements for its synthesis and isolation. Presented herein is the development work leading to a practical and scalable route for compound <b>2</b> starting from commercial dG. Salient features of the approach included one-pot protection of 5′-OH group of <i>N</i><sup>2</sup>-Tac-dG (<b>3</b>) with 4,4′-dimethoxytrityl (DMT) group followed by 3′-<i>O</i>-Tac protection furnishing fully protected dG <b>8</b>, thus reducing the cycle time with fewer isolation steps and lowering the solvent usage. Subsequently, cleavage of DMT group from <b>8</b> utilizing NaIO<sub>4</sub> enabled a mild, highly selective, and robust route to produce high purity (>99%) Bis-Tac-dG on kilogram-scale. The structure and origin of major impurities were determined by comparison with reference standards and carefully controlled to an acceptable level in compound <b>2</b>. The improved synthesis was scaled to prepare multiple ∼60 kg batches of <b>2</b> to supply all clinical studies up to phase III.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.1000,"publicationDate":"2024-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Organic Process Research & Development","FirstCategoryId":"92","ListUrlMain":"https://pubs.acs.org/doi/10.1021/acs.oprd.4c00073","RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, APPLIED","Score":null,"Total":0}
引用次数: 0
Abstract
Guadecitabine (SGI-110) is a dinucleotide that is a prodrug of decitabine. The dinucleotide contains decitabine (top fragment) and 2′-deoxyguanosine (9; dG; bottom fragment) connected via a 3′ → 5′ phosphodiester bond. The manufacturing process of guadecitabine requires a large quantity of N2, 3′-O-(4-tert-butylphenoxyacetyl)-protected dG (2; Bis-Tac-dG) to incorporate the bottom fragment. The protected 2 being a critical starting material of the dinucleotide imposes stringent quality requirements for its synthesis and isolation. Presented herein is the development work leading to a practical and scalable route for compound 2 starting from commercial dG. Salient features of the approach included one-pot protection of 5′-OH group of N2-Tac-dG (3) with 4,4′-dimethoxytrityl (DMT) group followed by 3′-O-Tac protection furnishing fully protected dG 8, thus reducing the cycle time with fewer isolation steps and lowering the solvent usage. Subsequently, cleavage of DMT group from 8 utilizing NaIO4 enabled a mild, highly selective, and robust route to produce high purity (>99%) Bis-Tac-dG on kilogram-scale. The structure and origin of major impurities were determined by comparison with reference standards and carefully controlled to an acceptable level in compound 2. The improved synthesis was scaled to prepare multiple ∼60 kg batches of 2 to supply all clinical studies up to phase III.
期刊介绍:
The journal Organic Process Research & Development serves as a communication tool between industrial chemists and chemists working in universities and research institutes. As such, it reports original work from the broad field of industrial process chemistry but also presents academic results that are relevant, or potentially relevant, to industrial applications. Process chemistry is the science that enables the safe, environmentally benign and ultimately economical manufacturing of organic compounds that are required in larger amounts to help address the needs of society. Consequently, the Journal encompasses every aspect of organic chemistry, including all aspects of catalysis, synthetic methodology development and synthetic strategy exploration, but also includes aspects from analytical and solid-state chemistry and chemical engineering, such as work-up tools,process safety, or flow-chemistry. The goal of development and optimization of chemical reactions and processes is their transfer to a larger scale; original work describing such studies and the actual implementation on scale is highly relevant to the journal. However, studies on new developments from either industry, research institutes or academia that have not yet been demonstrated on scale, but where an industrial utility can be expected and where the study has addressed important prerequisites for a scale-up and has given confidence into the reliability and practicality of the chemistry, also serve the mission of OPR&D as a communication tool between the different contributors to the field.