Scalable Synthesis of a Nucleoside Phosphoramidate Prodrug Inhibitor of HCV NS5B RdRp: Challenges in the Production of a Diastereomeric Mixture
A scalable process is described for the synthesis of 2′-C-methylguanosine-5′-[2-[(3-hydroxy-2,2-dimethyl-1-oxopropyl)thio]ethyl-N-benzylphosphoramidate], a nucleotide prodrug inhibitor of hepatitis C virus NS5B polymerase. The route features the use of phenylboronic acid to transiently protect...
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Veröffentlicht in: | Organic process research & development 2015-04, Vol.19 (4), p.520-530 |
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creator | Mayes, Benjamin A Wang, Jingyang Arumugasamy, Jeevanandam Arunachalam, Kannan Baloglu, Erkan Bauer, David Becker, Alan Chaudhuri, Narayan Glynn, Roberta Latham, G. Mark Li, Jie Lim, Jinsoo Liu, Jia Mathieu, Steve McGarry, F. Patrick Rosinovsky, Elodie Soret, Adrien F Stewart, Alistair Moussa, Adel |
description | A scalable process is described for the synthesis of 2′-C-methylguanosine-5′-[2-[(3-hydroxy-2,2-dimethyl-1-oxopropyl)thio]ethyl-N-benzylphosphoramidate], a nucleotide prodrug inhibitor of hepatitis C virus NS5B polymerase. The route features the use of phenylboronic acid to transiently protect the 2′,3′-hydroxyls of 2′-C-methylguanosine under mild conditions. The requirement to produce a 1:1 phosphorus diastereomeric mixture precluded the use of traditional crystallization techniques. High sensitivity of the drug substance to acidic and basic conditions and its preferred solubility in mixed aqueous–organic solvents presented additional processing challenges. The use of reverse phase chromatography for the final purification was eliminated by the development of a dual liquid–liquid extraction protocol, which removed both non-polar and polar impurities whilst maintaining the 1:1 diastereomeric ratio. Ethylene sulfide, a potential genotoxic impurity that was observed at significant levels in the original procedure, was controlled to 99% purity in the requisite 1:1 diastereomeric ratio. |
doi_str_mv | 10.1021/op5003837 |
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Mark ; Li, Jie ; Lim, Jinsoo ; Liu, Jia ; Mathieu, Steve ; McGarry, F. Patrick ; Rosinovsky, Elodie ; Soret, Adrien F ; Stewart, Alistair ; Moussa, Adel</creator><creatorcontrib>Mayes, Benjamin A ; Wang, Jingyang ; Arumugasamy, Jeevanandam ; Arunachalam, Kannan ; Baloglu, Erkan ; Bauer, David ; Becker, Alan ; Chaudhuri, Narayan ; Glynn, Roberta ; Latham, G. Mark ; Li, Jie ; Lim, Jinsoo ; Liu, Jia ; Mathieu, Steve ; McGarry, F. Patrick ; Rosinovsky, Elodie ; Soret, Adrien F ; Stewart, Alistair ; Moussa, Adel</creatorcontrib><description>A scalable process is described for the synthesis of 2′-C-methylguanosine-5′-[2-[(3-hydroxy-2,2-dimethyl-1-oxopropyl)thio]ethyl-N-benzylphosphoramidate], a nucleotide prodrug inhibitor of hepatitis C virus NS5B polymerase. The route features the use of phenylboronic acid to transiently protect the 2′,3′-hydroxyls of 2′-C-methylguanosine under mild conditions. The requirement to produce a 1:1 phosphorus diastereomeric mixture precluded the use of traditional crystallization techniques. High sensitivity of the drug substance to acidic and basic conditions and its preferred solubility in mixed aqueous–organic solvents presented additional processing challenges. The use of reverse phase chromatography for the final purification was eliminated by the development of a dual liquid–liquid extraction protocol, which removed both non-polar and polar impurities whilst maintaining the 1:1 diastereomeric ratio. Ethylene sulfide, a potential genotoxic impurity that was observed at significant levels in the original procedure, was controlled to <10 ppm in the final product. 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The route features the use of phenylboronic acid to transiently protect the 2′,3′-hydroxyls of 2′-C-methylguanosine under mild conditions. The requirement to produce a 1:1 phosphorus diastereomeric mixture precluded the use of traditional crystallization techniques. High sensitivity of the drug substance to acidic and basic conditions and its preferred solubility in mixed aqueous–organic solvents presented additional processing challenges. The use of reverse phase chromatography for the final purification was eliminated by the development of a dual liquid–liquid extraction protocol, which removed both non-polar and polar impurities whilst maintaining the 1:1 diastereomeric ratio. Ethylene sulfide, a potential genotoxic impurity that was observed at significant levels in the original procedure, was controlled to <10 ppm in the final product. 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Patrick</au><au>Rosinovsky, Elodie</au><au>Soret, Adrien F</au><au>Stewart, Alistair</au><au>Moussa, Adel</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Scalable Synthesis of a Nucleoside Phosphoramidate Prodrug Inhibitor of HCV NS5B RdRp: Challenges in the Production of a Diastereomeric Mixture</atitle><jtitle>Organic process research & development</jtitle><addtitle>Org. Process Res. Dev</addtitle><date>2015-04-17</date><risdate>2015</risdate><volume>19</volume><issue>4</issue><spage>520</spage><epage>530</epage><pages>520-530</pages><issn>1083-6160</issn><eissn>1520-586X</eissn><abstract>A scalable process is described for the synthesis of 2′-C-methylguanosine-5′-[2-[(3-hydroxy-2,2-dimethyl-1-oxopropyl)thio]ethyl-N-benzylphosphoramidate], a nucleotide prodrug inhibitor of hepatitis C virus NS5B polymerase. The route features the use of phenylboronic acid to transiently protect the 2′,3′-hydroxyls of 2′-C-methylguanosine under mild conditions. The requirement to produce a 1:1 phosphorus diastereomeric mixture precluded the use of traditional crystallization techniques. High sensitivity of the drug substance to acidic and basic conditions and its preferred solubility in mixed aqueous–organic solvents presented additional processing challenges. The use of reverse phase chromatography for the final purification was eliminated by the development of a dual liquid–liquid extraction protocol, which removed both non-polar and polar impurities whilst maintaining the 1:1 diastereomeric ratio. Ethylene sulfide, a potential genotoxic impurity that was observed at significant levels in the original procedure, was controlled to <10 ppm in the final product. This process produced 20 kg of drug substance in 59% overall yield, with >99% purity in the requisite 1:1 diastereomeric ratio.</abstract><pub>American Chemical Society</pub><doi>10.1021/op5003837</doi><tpages>11</tpages></addata></record> |
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title | Scalable Synthesis of a Nucleoside Phosphoramidate Prodrug Inhibitor of HCV NS5B RdRp: Challenges in the Production of a Diastereomeric Mixture |
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