Details for Patent: 5,760,202

Title:	Process for the synthesis of 2'-O-substituted pyrimidines
Abstract:	Improved processes for the synthesis of 2'-O-substituted pyrimidine nucleosides are provided. The processes feature alkylation of a 2,2'-anhydropyrimidine nucleoside or a 2S,2'-anhydropyrimidine nucleoside with a weak nucleophile in the presence of a Lewis acid.
Inventor(s):	Cook; Phillip Dan (San Marcos, CA), Springer; Robert H. (Carlsbad, CA), Sprankle; Kelly G. (Vista, CA), Ross; Bruce S. (Carlsbad, CA)
Assignee:	Isis Pharmaceuticals, Inc. (Carlsbad, CA)
Filing Date:	Jun 07, 1995
Application Number:	08/475,467
Claims:	1. A process for the synthesis of a 2'-O-substituted pyrimidine nucleoside of formula: ##STR5## wherein: Q is a pyrimidine base or a 2-S pyrimidine base; R.sup.1 is substituted or unsubstituted C.sub.1 -C.sub.30 alkyl, C.sub.1 -C.sub.30 alkenyl, C.sub.1 -C.sub.30 alkynyl, C.sub.6 -C.sub.14 aryl, or C.sub.7 -C.sub.30 aralkyl, wherein said substitution is halo, amino, hydroxyl, thiol, ether or thioether; and R.sup.2 and R.sup.3 are independently hydrogen or a hydroxyl protecting group; comprising the steps of: providing a 2-2'-anhydropyrimidine nucleoside; selecting an alcohol of the formula R.sup.1 --OH; and treating said 2-2'-anhydropyrimidine nucleoside and said alcohol with a Lewis acid under conditions of time, temperature and pressure effective to yield said 2'-O-substituted pyrimidine nucleoside; wherein said Lewis acid is a borate. 2. The process of claim 1 wherein said borate is a trialkyl borate. 3. The process of claim 2 wherein the formula of said trialkyl borate is B(OR.sup.1).sub.3. 4. The process of claim 3 wherein said trialkyl borate is prepared from the treatment of borane with an alcohol. 5. A process for the synthesis of a 2'-O-substituted cytidine nucleoside of formula: ##STR6## wherein: X is O or S; R.sup.1 is substituted or unsubstituted C.sub.1 -C.sub.30 alkyl, C.sub.1 -C.sub.30 alkenyl, C.sub.1 -C.sub.30 alkynyl, C.sub.6 -C.sub.14 aryl, or C.sub.7 -C.sub.30 aralkyl, wherein said substitution is halo, amino, hydroxyl, thiol, ether or thioether; R.sup.2 and R.sup.3 are independently hydrogen or a hydroxyl protecting group; R.sup.5 and R.sup.6 are independently H, C.sub.1 -C.sub.30 hydrocarbyl or substituted C.sub.1 -C.sub.30 hydrocarbyl; comprising the steps of: providing a 2-2'-anhydrouridine nucleoside of formula: ##STR7## selecting an alcohol of formula R.sup.1 --OH; treating said 2-2'-anhydrouridine nucleoside and said alcohol with a Lewis acid under conditions of time, temperature and pressure effective to form a 2'-O-substituted uridine nucleoside; and aminating said 2'-O-substituted uridine nucleoside to form said 2'-O-substituted cytidine nucleoside; wherein said Lewis acid is a borate. 6. The process of claim 5 wherein said borate is a trialkyl borate. 7. The process of claim 6 wherein the formula of said trialkyl borate is B(OR.sup.1).sub.3. 8. The process of claim 6 wherein said trialkyl borate is prepared from the treatment of borane with an alcohol.