Compounds, processes and intermediates for synthesis of mixed backbone oligomeric compounds
AssigneeIsis Pharmaceuticals, Inc.
InventorsMuthiah Manoharan, Martin A. Maier
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Abstract
Synthetic processes are provided wherein mixed backbone oligomeric compounds are prepared having at least one phosphodiester intemucleoside linkage in addition to one or more phosphorothioate, phosphoramidate and boranophosphate internucleoside linkages. Novel H-phosphonate intermediates are also disclosed that are useful in the synthetic processes. The synthetic processes use a novel oxidation step to oxidize H-phosphonate internuleoside linkages to phosphodiester internuleoside linkages without degradation of adjacent phosphorothioate, phosphoramidate and boranophosphate internucleoside linkages. Also provided are synthetic intermediates useful in such processes.
Claims40
A method of preparing an oligomeric compound of formula:
- wherein:
- each Z is, independently, a phosphodiester, phosphorothioate, phosphoramidate or boranophosphate internucleoside linkage;
- each T1 and T2 is, independently, hydroxyl or a protected hydroxyl;
- Bx is a heterocyclic base moiety;
- each R1 is, independently, H, hydroxyl, a protected hydroxyl, a 2′-substituent group or a protected 2′-substituent group;
- and
- n is an integer greater than 1;
- provided that at least one of said Z is phosphodiester and at least another of said Z is a phosphorothioate, phosphoramidate or boranophosphate internucleoside linkage;
- comprising the steps of:
- (a) providing a compound of formula:
- wherein:
- Pg is an acid labile hydroxyl protecting group;
- and
- T3 is a base labile hydroxyl protecting group or a covalent attachment to a solid support;
- (b) deblocking said acid labile hydroxyl protecting group to form a deblocked hydroxyl group;
- (c) treating said deblocked hydroxyl group with a further compound having the formula:
- and a condensing reagent in a solvent under conditions of time, temperature and pressure effective to form an extended compound having an added H-phosphonate internucleoside linkage;
- (d) optionally treating said extended compound with a capping agent to form a capped compound;
- (e) optionally treating said capped compound with a silylating agent to give a silylated compound;
- (f) optionally repeating steps (b), (c), (d) and (e);
- (g) treating said extended compound, said capped compound, or said silylated compound with an oxidizing solution inert to a phosphodiester, phosphorothioate, phosphoramidate or boranophosphate internucleoside linkage, thereby oxidizing said H-phosphonate internucleoside linkages to phosphodiester, phosphorothioate, phosphoramidate or boranophosphate internucleoside linkages;
- (h) optionally repeating steps (b), (c), (d), (e), (f), and (g) to form a protected oligomeric compound;
- and
- (i) treating said protected oligomeric compound with a deblocking solution to form said oligomeric compound.
Dependencies are inferred from the claim text.