Oligomer phosphoramidite compositions and processes for synthesizing the same
원문보기
IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
C07H-021/00
C07H-021/02
출원번호
US-0444445
(2003-05-23)
발명자
/ 주소
Ravikumar, Vasulinga T.
Capaldi, Daniel C.
Cole, Douglas L.
출원인 / 주소
Isis Pharmaceuticals, Inc.
대리인 / 주소
Isis Patent Department
인용정보
피인용 횟수 :
0인용 특허 :
25
초록
Synthetic processes are provided wherein oligomers are prepared using phosphoramidite compositions. Oligomers having phosphodiester, phosphorothioate, phosphorodithioate covalent linkages are prepared that can include other covalent linkages. Also provided are compositions useful in such processes.
대표청구항▼
1. A method of preparing an oligomer having at least one moiety of formula: wherein:each X1 and X2 is, independently, O or S; Bx is a protected or unprotected heterocyclic base moiety; and R1 is H, a protected hydroxyl group, a sugar substituent group, or a protected sugar substituent group; compris
1. A method of preparing an oligomer having at least one moiety of formula: wherein:each X1 and X2 is, independently, O or S; Bx is a protected or unprotected heterocyclic base moiety; and R1 is H, a protected hydroxyl group, a sugar substituent group, or a protected sugar substituent group; comprising the steps of:(a) providing a compound having one of the formulas: wherein:T1 is a hydroxyl protecting group; and T2 is a covalent attachment to a solid support or a solid support bound nucleoside, nucleotide, oligonucleoside or oligonucleotide; (b) removing the T1 group to form said compound having a 5′-hydroxyl group; and (c) treating said compound having a 5′-hydroxyl group with a phosphoramidite composition to form an extended compound, said phosphoramidite composition comprising a phosphoramidite compound of the formula: wherein:T1 is a protected hydroxyl group, a nucleoside, a nucleotide, an oligonucleoside or an oligonucleotide; R0 is a phosphorus protecting group; and each L1 and L2 is, independently, C1-6 alkyl; or L1 and L2 are joined together to form a 4- to 7-membered heterocyclic ring system including the nitrogen atom to which said L1 and L2 are attached, said ring system optionally including at least one additional heteroatom selected from O, N and S; said phosphoramidite composition further comprising at least about 1% by weight of at least one 2′-hydroxy nucleoside, a PIII species different from said phosphoramidite compound where covalent attachment of groups to the PIII phosphorus of said PIII species is through oxygen or sulfur, or a PV species where covalent attachment of groups to the PV species is through oxygen, sulfur or nitrogen. 2. The method of claim 1 wherein said phosphoramidite composition comprises at least about 2% by weight of at least one 2′-hydroxy nucleoside, a PIII species different from said phosphoramidite compound where covalent attachment of groups to the PIII phosphorus of said PIII species is through oxygen or sulfur, or a PV species where covalent attachment of groups to the PV species is through oxygen, sulfur or nitrogen.3. The method of claim 1 further comprising treating said extended compound with a capping agent to form a capped compound.4. The method of claim 3 further comprising treating said capped compound with an oxidizing agent to form an oxidized compound.5. The method of claim 4 further comprising treating said oxidized compound with a reagent effective to deprotect said oxidized compound to form a deprotected oligomer.6. The method of claim 5 further comprising treating said deprotected oligomer with a reagent effective to cleave said oligomer from the solid support.7. The method of claim 1 further comprising treating said extended compound with a reagent effective to remove the protecting group from said protected hydroxyl group.8. The method of claim 1 wherein said composition includes at least one compound having one of the formulas: wherein:each X2 is, independently, O or S; each J is CH2CH2CN, diphenylsilylethyl, δ-cyanobutenyl, cyano p-xylyl (CPX), methyl-N-trifluoroacetyl ethyl (META) or acetoxy phenoxy ethyl (APOE); each T4 is, independently, a hydroxyl group or a protected hydroxyl group; each R0 is a phosphorus protecting group, each L1 and L2 is, independently, C1-6 alkyl; or L1 and L2 are joined together with the nitrogen atom to which said L1 and L2 are attached to form a 4- to 7-membered heterocyclic ring system, wherein said ring system optionally includes at least one additional heteroatom selected from O, N and S; each Bx is a protected or unprotected heterocyclic base moiety; and each R1 is, independently, H, a protected hydroxyl group, a sugar substituent group, or a protected sugar substituent group. 9. The method of claim 1 wherein said phosphoramidite composition comprises at least about 98% by weight of said phosphoramidite compound.10. The method of claim 1 wherein said phosphoramidite composition comprises at least about 97% by weight of said phosphoramidite compound.11. The method of claim 1 wherein said phosphoramidite composition comprises at least about 95% by weight of said phosphoramidite compound.12. The method of claim 1 wherein said phosphoramidite composition comprises at least about 90% by weight of said phosphoramidite compound.13. The method of claim 1 wherein said phosphoramidite composition comprises at least about 80% by weight of said phosphoramidite compound.14. The method of claim 1 wherein said phosphoramidite composition comprises at least about 75% by weight of said phosphoramidite compound.15. A composition comprising at least one phosphoramidite compound of the formula: wherein:T3 is a protected hydroxyl group, a nucleoside, a nucleotide, an oligonucleoside or an oligonucleotide; Bx is a protected or unprotected heterocyclic base moiety; each R1 is, independently, H, a protected hydroxyl group, a sugar substituent group or a protected sugar substituent group; R0 is a phosphorus protecting group; and each L1 and L2 is, independently, C1-6 alkyl; or L1 and L2 are joined together to form a 4- to 7-membered heterocyclic ring system including the nitrogen atom to which L1 and L2 are attached, wherein said ring system optionally includes at least one additional heteroatom selected from O, N and S; and said composition further comprising at least about 1% by weight of at least one 3′-hydroxy nucleoside, 2′-hydroxy nucleoside, PIII species different from said phosphoramidite compound where covalent attachment of groups to the PIII phosphorus of said PIII species is through oxygen or sulfur, or a PV species where covalent attachment of groups to the PV species is through oxygen, sulfur or nitrogen. 16. The composition of claim 15 wherein said composition comprises at least about 2% by weight of at least one 3′-hydroxy nucleoside, 2′-hydroxy nucleoside, PIII species different from said phosphoramidite compound where covalent attachment of groups to the PIII phosphorus of said PIII species is through oxygen or sulfur, or a PV species where covalent attachment of groups to the PV species is through oxygen, sulfur or nitrogen.17. The composition of claim 15 including at least one compound having one of the formulas: wherein:each X2 is, independently, O or S; each J is CH2CH2CN, diphenylsilylethyl, δ-cyanobutenyl, cyano p-xylyl (CPX), methyl-N-trifluoroacetyl ethyl (META) or acetoxy phenoxy ethyl (APOE); each T4 is, independently, a hydroxyl group or a protected hydroxyl group; each R0 is a phosphorus protecting group; each L1 and L2 is, independently, C1-6 alkyl; or L1 and L2 are joined together with the nitrogen atom to which said L1 and L2 are attached to form a 4- to 7-membered heterocyclic ring system, wherein said ring system optionally includes at least one additional heteroatom selected from O, N and S; each Bx is a protected or unprotected heterocyclic base moiety; and each R1 is, independently, H, a protected hydroxyl group, a sugar substituent group, or a protected sugar substituent group. 18. A composition comprising at least one phosphoramidite compound of the formula: wherein:T3 is a protected hydroxyl group, a nucleoside, a nucleotide, an oligonucleoside or an oligonucleotide; Bx is a protected or unprotected heterocyclic base moiety: each R1 is, independently, H, a protected hydroxyl group, a sugar substituent group or a protected sugar substituent group; R0 is a phosphorus protecting group; and each L1 and L2 is, independently, C1-6 alkyl; or L1 and L2 are joined together to form a 4- to 7-membered heterocyclic ring system with the nitrogen atom to which L1 and L2 are attached, wherein said ring system optionally includes at least one additional heteroatom selected from O, N and S; said composition further comprising at least about 1% by weight of at least one 3′-hydroxy nucleoside, 2′-hydroxy nucleoside, PIII species different from said phosphoramidite compound where covalent attachment of groups to the PIII phosphorus of said PIII species is through oxygen or sulfur, or a PV species where covalent attachment of groups to the PV species is through oxygen, sulfur or nitrogen. 19. The composition of claim 18 comprising at least about 2% by weight of at least one 3′-hydroxy nucleoside, 2′-hydroxy nucleoside, PIII species different from said phosphoramidite compound where covalent attachment of groups to the PIII phosphorus of said PIII species is through oxygen or sulfur, or a PV species where covalent attachment of groups to the PV species is through oxygen, sulfur or nitrogen.20. The composition of claim 18 including at least one compound having one of the formulas: wherein:each X2 is, independently, O or S; each J is CH2CH2CN, diphenylsilylethyl, δ-cyanobutenyl, cyano p-xylyl (CPX), methyl-N-trifluoroacetyl ethyl (META) or acetoxy phenoxy ethyl (APOE); each T4 is, independently, a hydroxyl group or a protected hydroxyl group; each R0 is a phosphorus protecting group, each L1 and L2 is, independently, C1-6 alkyl; or L1 and L2 are joined together to form a 4- to 7-membered heterocyclic ring system including the nitrogen atom to which said L1 and L2 are attached, wherein said ring system optionally includes at least one additional heteroatom selected from O, N and S; each Bx is a protected or unprotected heterocyclic base moiety; and each R1 is, independently, H, a protected hydroxyl group, a sugar substituent group, or a protected sugar substituent group. 21. The composition of claim 18 comprising at least about 98% by weight of said phosphoramidite compound.22. The composition of claim 18 comprising at least about 97% by weight of said phosphoramidite compound.23. The composition of claim 18 comprising at least about 95% by weight of said phosphoramidite compound.24. The composition of claim 18 comprising at least about 90% by weight of said phosphoramidite compound.25. The composition of claim 18 comprising at least about 80% by weight of said phosphoramidite compound.26. The composition of claim 18 comprising at least about 75% by weight of said phosphoramidite compound.27. A composition comprising at least one phosphoramidite compound of the formula: wherein:T3 is a protected hydroxyl group, a nucleoside, a nucleotide, an oligonucleoside or an oligonucleotide; Bx is a protected or unprotected heterocyclic base moiety; each R1 is, independently, H, a protected hydroxyl group, a sugar substituent group or a protected sugar substituent group; R0 is a phosphorus protecting group; and each L1 and L2 is, independently, C1-6 alkyl; or L1 and L2 are joined together to form a 4- to 7-membered heterocyclic ring system including the nitrogen atom to which said L1 and L2 are attached, wherein said ring system optionally includes at least one additional heteroatom selected from O, N and S; and said composition further comprising at least about 1% by weight of at least one PIII species different from said phosphoramidite compound where covalent attachment of groups to the PIII phosphorus of said PIII species is through oxygen or sulfur, or a PV species where covalent attachment of groups to the PV species is through oxygen, sulfur or nitrogen. 28. The composition of claim 27 comprising at least about 2% by weight of at least one PIII species different from said phosphoramidite compound where covalent attachment of groups to the PIII phosphorus of said PIII species is through oxygen or sulfur, or a PV species where covalent attachment of groups to the PV species is through oxygen, sulfur or nitrogen.29. The composition of claim 27 comprising at least about 98% by weight of said phosphoramidite compound.30. The composition of claim 27 comprising at least about 97% by weight of said phosphoramidite compound.31. The composition of claim 27 comprising at least about 95% by weight of said phosphoramidite compound.32. The composition of claim 27 comprising at least about 90% by weight of said phosphoramidite compound.33. The composition of claim 27 comprising at least about 80% by weight of said phosphoramidite compound.34. The composition of claim 27 comprising at least about 75% by weight of said phosphoramidite compound.
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이 특허에 인용된 특허 (25)
Manoharan Muthiah ; Cook Phillip Dan ; Prakash Thazha P. ; Kawasaki Andrew M., Aminooxy-modified oligonucleotides and methods for making same.
Andrus William A. (San Francisco CA) Efcavitch J. William (Belmont CA) McBride Lincoln J. (Redwood City CA), Chemical capping by phosphitylation during oligonucleotide synthesis.
Froehler Brian C. (2310 Monserat Ave. Belmont CA 94002) Kent Kenneth M. (1725 Wright Ave. 63 Mt. View CA 94043) Wu Sylvia (6050 Mount Rushmore Cir. Castro Valley CA 94552), Monomethoxytrityl protected oligonucleotides bound to a solid support.
Cook Phillip Dan ; Sanghvi Yogesh S. ; Sprankle Kelly G. ; Ross Bruce S. ; Griffey Rich H., Oligomeric compounds having pyrimidine nucleotide (S) with 2'and 5 substitutions.
Caruthers Marvin H. (Boulder CO) Marshall William S. (Boulder CO) Brill Wolfgang (Freiburg DEX) Nielsen John (Horsholm DKX), Polynucleotide phosphorodithioate.
Ravikumar Vasulinga T. (Carlsbad CA) Mulvey Dennis (Vista CA) Cole Douglas L. (San Diego CA) Cook Phillip D. (Carlsbad CA), Process for preparing oligonucleotides using silyl-containing diamino phosphorous reagents.
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