title: Kilo-scale synthesis process for 2'-O-(2-methoxyethyl)-pyrimidine derivatives.
abstract: We describe an improved process to produce 2'-O-(2-methoxyethyl)-pyrimidines. Starting with commercially available O-2,2'-anhydro-5-methyluridine and tris-(2-methoxyethyl)borate, we modified the ring-opening reaction conditions and changed to a continuous extraction purification method to give 2'-O-(2-methaxyethyl)-5-methyluridine. The dimethoxytritylation 5'/3' ratios and yield were improved by the use of 2,6-lutidine as the base. Conditions to convert to the 5'-methylcytidine analog and its isolation by crystallization were optimized. Final benzoylation was improved by developing a method to selectively hydrolyze benzoyl ester impurities.
authors.affiliation: Isis Pharmaceuticals, 2292 Faraday Ave., Carlsbad, CA 92008, USA.
authors.forename: Bruce S
authors.initials: BS
authors.lastname: Ross
authors.forename: Quanlai
authors.initials: Q
authors.lastname: Song
authors.forename: Mingming
authors.initials: M
authors.lastname: Han
mesh_terms: D001896:Boron Compounds / Q000737:chemistry; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D002845:Chromatography; D003562:Cytidine / Q000031:analogs & derivatives / Q000737:chemistry; D004952:Esters; D006868:Hydrolysis; D008956:Models, Chemical; D011725:Pyridines / Q000737:chemistry; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry*; D014529:Uridine / Q000031:analogs & derivatives / Q000737:chemistry
chemical_list: D001896:Boron Compounds; D004952:Esters; D011725:Pyridines; D011743:Pyrimidines; C009182:ribothymidine; C013093:2,6-lutidine; D003562:Cytidine; C016568:5-methylcytidine; D014529:Uridine