Patent ID: 6399756
Filing Date: 2002-06-04
Classification: C07H,Y02P

Abstract:
A method for the preparation of an oligomeric compound comprising a moiety having the formula I: wherein:the phosphorus is attached through the oxygen to an oligonucleotide or an analog thereof; A is a diradical derived from a monocyclic or bicyclic aromatic ring system; R11 and R12 are each independently selected from the group consisting of H, alkyl, aryl, heteroalkyl, heteroaryl, alkaryl, and aralkyl; or R11 and R12 together with the carbon atoms to which they are attached form an optionally substituted aliphatic or aromatic ring having from 4 to 6 ring atoms; X4 is selected from the group consisting of alkaryl, aralkyl, sulfonyl, thio, substituted sulfonyl, and substituted thio, wherein said substituent is alkyl, aryl, or alkaryl; or X4 is a group of formula â€”C(&boxH;O)-(O)aa-R40 where aa is 0 or 1 and R40 is selected from the group consisting of lower alkyl, aryl, aralkyl, and heteroaryl wherein said lower alkyl, aryl, aralkyl or heteroaryl groups are optionally substituted with one or more alkyl, aryl, aralkyl, halo or acetyl groups; or X4 is a group of formula â€”(â€”CH2â€”CH2â€”)dSi(R9)3 where d is 0 or 1; each R9 is, independently, alkyl having 1 to about 10 carbon atoms, or aryl having 6 to about 10 carbon atoms; X1 and X5 are each independently O or S; comprising: (a) providing a compound having the Formula II: wherein:each R1, is, independently, selected from the group consisting of H, hydroxyl, C1-C20 alkyl, C3-C20 alkenyl, C2-C20 alkynyl, halogen, keto, carboxyl, nitro, nitroso, trifluoromethyl, trifluoromethoxy, O-alkyl, S-alkyl, NH-alkyl, N-dialkyl, O-aryl, S-aryl, NH-aryl, O-aralkyl, S-aralkyl, NH-aralkyl, amino, N-phthalimido, azido, hydrazino, hydroxylamino, isocyanato, silyl, aryl, and a radical or diradical derived from a polyamine, polyamide, polyalkylene glycol, polyether, thiol, nitrile, imidazole, sulfoxide, sulfone, sulfide or disulfide; or R1 is a group of formula Z-R22-(R23)v; Z is O, S, NH, or N-R22-(R23)v; R22 is C1-C20 alkylene, C2-C20 alkenylene, or C2-C20 alkynylene; R23 is selected from the group consisting of hydrogen, amino, halogen, hydroxyl, thio, keto, carboxyl, nitrilo, trifluoromethyl, trifluoromethoxy, O-alkyl, S-alkyl, NH-alkyl, N-dialkyl, O-aryl, S-aryl, NH-aryl, O-aralkyl, S-aralkyl, NH-aralkyl, N-phthalimido, imidazolyl, azido, hydrazino, hydroxylamino, isocyanate, sulfonyl, sulfidyl, silyl, aryl, and a radical or diradical derived from a polyamine, polyamide, polyalkylene glycol, or polyether, v is from 0 to about 10; or R1 has the formula: wherein: y1 is 0 or 1; y2 is independently 0 to 10; y3 is 1 to 10; E is C1-C10 alkyl, N(Q1)(Q2) or N&boxH;C(Q1)(Q2); each Q1 and Q2 is, independently, selected from the group consisting of H, C1-C10 alkyl, substituted C1-C10 alkyl, dialkylaminoalkyl, a nitrogen protecting group, a tethered or untethered conjugate group, and a linker to a solid support; or Q1 and Q2, together, are joined in a nitrogen protecting group or a ring structure that can include at least one additional heteroatom selected from N and O; or R1 has one formula XI or XII: whereinZ0 to O, S, or NH; q1 is from 0 to 10; q2 is from 1 to 10; q3 is 0 or 1; q4 is 0, 1 or 2; Z4 is OH1, SM1, or N(M1)2; each M1 is, independently, selected from the group consisting of H, C1-C8 alkyl, C1-C8 haloalkyl, C(&boxH;NH)N(H)M2, C(&boxH;O)N(H)M2 and OC(&boxH;O)N(H)M2; M2 is H or C1-C8 alkyl; Z1, Z2 and Z3 form a ring system having from about 4 to about 7 carbon atoms, or having from about 3 to about 6 carbon atoms and 1 or 2 heteroatoms wherein said heteroatoms are selected from the group consisting of oxygen, nitrogen and sulfur, and wherein said ring system is aliphatic, unsaturated aliphatic, aromatic, or saturated or unsaturated heterocyclic; and Z5 is alkyl or haloalkyl having 1 to about 10 carbon atoms, alkenyl having 2 to about 10 carbon atoms, alkynyl having 2 to about 10 carbon atoms, aryl having 6 to about 14 carbon atoms, N(Q1)(Q2), OQ1, halo, SQ1 or CN; R3 is hydrogen, a hydroxyl protecting group, or a linker connected to a solid support; each B, independently, is a naturally occurring or non-naturally occurring nucleobase or a protected naturally occurring or non-naturally occurring nucleobase; n is 0 to about 50; M is an optionally protected internucleoside linkage; R5 is â€”N(R6)2, or a heterocycloalkyl or heterocycloalkenyl ring containing from 4 to 7 atoms, and having up to 3 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen; and R6 is straight or branched chain alkyl having from 1 to 10 carbons; and (b) reacting the compound of Formula II with a compound having Formula III: wherein m is 0 to about 50; R3a is hydrogen; R2 is selected from the group consisting of hydrogen, a hydroxyl protecting group, and a linker connected to a solid support, provided that R2 and R3 are not both simultaneously a linker connected to a solid support; to form the oligomeric compound.