Processes for the synthesis of oligomeric compounds

A method for preparing a phosphoramidite of Formula:

• 42
• wherein:
• R3 is hydrogen, a hydroxyl protecting group, or a linker connected to a solid support;
• Z is aryl having 6 to about 14 carbon atoms or alkyl having from one to about six carbon atoms;
• Y1 is O or S;
• Y2 is O or S;
• Y3 is C(═O) or S;
• q is 2 to about 4;
• M is an optionally protected internucleotide linkage;
• each B, independently is a naturally occurring or non-naturally occurring nucleobase that is optionally protected and optionally radiolabeled;
• n is 0 to about 50;
• R1 is H, OH, F, or a group of formula R7—(R8)n;
• R7 is C3-C20 alkyl, C4-C2, alkenyl, C2-C20 alkynyl, C1-C20 alkoxy, C2-C20 alkenyloxy, or C2-C20 alkynyloxy;
• R8 is hydrogen, amino, protected amino, halogen, hydroxyl, thiol, keto, carboxyl, nitro, nitroso, nitrile, trifluoromethyl, trifluoromethoxy, O-alkyl, S-alkyl, NH-alkyl, N-dialkyl, O-aryl, S-aryl, NH-aryl, O-aralkyl, S-aralkyl, NH-aralkyl, N-phthalimido, imidazole, azido, hydrazino, hydroxylamino, isocyanato, sulfoxide, sulfone, sulfide, disulfide, silyl, aryl, heterocycle, carbocycle, intercalator, reporter molecule, conjugate, polyamine, polyamide, polyalkylene glycol, polyether, a group that enhances the pharmacodynamic properties of oligonucleotides, a group that enhances the pharmacokinetic properties of oligonucleotides, or a group of formula (—O—X3)p, where p is 1 to about 10 and X3 is alkyl having from one to about 10 carbons;
• R5 is —N(R6)2, or a heterocycloalkyl or heterocycloalkenyl ring containing from 4 to 7 atoms and up to 3 heteroatoms selected from nitrogen, sulfur, and oxygen;
• R6 is straight or branched chain alkyl having from 1 to 10 carbons;
• comprising the steps of:
• providing a compound Formula:
• 43
• and reacting the compound with a diaminohalophosphine of Formula:
• 44
• wherein X is halogen;
• thereby providing a phosphordiamidite of Formula:
• 45
• and
• contacting the nucleoside phosphordiamidite with a reagent of Formula XX:
• 46
• to produce the phosphoramidite.

A method for preparing a phosphoramidite of Formula:

• 48
• wherein:
• R3 is hydrogen, a hydroxyl protecting group, or a linker connected to a solid support;
• Z is aryl having 6 to about 14 carbon atoms or alkyl having from one to about six carbon atoms;
• Y1 is O or S;
• Y2 is O or S;
• Y3 is C(═O) or S;
• M is an optionally protected internucleotide linkage;
• each B, independently is a naturally occurring or non-naturally occurring nucleobase that is optionally protected and optionally radiolabeled;
• n is 0 to about 50;
• R1 is H, OH, F, or a group of formula R7—(R8)n;
• R7 is C3-C10 alkyl, C4-C20 alkenyl, C2-C29 alkynyl, C1-C20 alkoxy, C2-C20 alkenyloxy, or C2-C20 alkynyloxy;
• R8 is hydrogen, amino, protected amino, halogen, hydroxyl, thiol, keto, carboxyl, nitro, nitroso, nitrile, trifluoromethyl, trifluoromethoxy, O-alkyl, S-alkyl, NH-alkyl, N-dialkyl, O-aryl, S-aryl, NH-aryl, O-aralkyl, S-aralkyl, NH-aralkyl, N-phthalimido, imidazole, azido, hydrazino, hydroxylamino, isocyanato, sulfoxide, sulfone, sulfide, disulfide, silyl, aryl, heterocycle, carbocycle, intercalator, reporter molecule, conjugate, polyamine, polyamide, polyalkylene glycol, polyether, a group that enhances the pharmacodynamic properties of oligonucleotides, a group that enhances the pharmacokinetic properties of oligonucleotides, or a group of formula (—O—X3)p, where p is 1 to about 10 and X3 is alkyl having from one to about 10 carbons;
• R5 is —N(R6)2, or a heterocycloalkyl or heterocycloalkenyl ring containing from 4 to 7 atoms and up to 3 heteroatoms selected from nitrogen, sulfur, and oxygen;
• R6 is straight or branched chain alkyl having from 1 to 10 carbons;
• comprising the steps of:
• providing a compound Formula:
• 49
• and reacting the compound with a compound of Formula:
• 50
• wherein:
• R5 is —N(R)6,2 or a heterocycloalkyl or heterocycloalkenyl ring containing from 4 to 7 atoms and up to 3 heteroatoms selected from nitrogen, sulfur, and oxygen;
• R6 is straight or branched chain alkyl having from 1 to 10 carbons;
• thereby producing the phosphordiamidite.