Oligonucleotide synthesis with alternative solvents
IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
C07H-021/00
C07H-021/02
C07H-021/04
C12Q-001/68
출원번호
US-0858917
(2004-06-02)
등록번호
US-7276599
(2007-10-02)
발명자
/ 주소
Moore,Max N.
Andrade,Mark
Carty,Recaldo
Scozzari,Anthony
Krotz,Achim
출원인 / 주소
Isis Pharmaceuticals, Inc.
대리인 / 주소
Woodcock Washburn LLP
인용정보
피인용 횟수 :
97인용 특허 :
166
초록▼
The invention provides for methods of manufacturing an oligonucleotide comprising a pentavalent phosphate triester. In particular, the method comprises providing a 5' blocked-nucleoside, deblocking the 5' blocked-nucleoside to form a 5' OH-nucleoside, coupling the 5' OH-nucleoside with a phosphorami
The invention provides for methods of manufacturing an oligonucleotide comprising a pentavalent phosphate triester. In particular, the method comprises providing a 5' blocked-nucleoside, deblocking the 5' blocked-nucleoside to form a 5' OH-nucleoside, coupling the 5' OH-nucleoside with a phosphoramidite to form and oligonucleotide comprising a trivalent phosphite triester; and oxidizing the oligonucleotide comprising a trivalent phosphite triester to the oligonucleotide comprising a pentavalent phosphate triester. In some embodiments, the wash between any of the steps above is with at least one solvent wash comprising a toluene.
대표청구항▼
What is claimed is: 1. A method of manufacturing an oligonucleotide comprising a pentavalent phosphate triester, said method comprising: (a) providing a 5' blocked-nucleoside; (b) deblocking the 5' blocked-nucleoside to form a 5' OH-nucleoside; (c) coupling the 5' OH-nucleoside with a phosphoramidi
What is claimed is: 1. A method of manufacturing an oligonucleotide comprising a pentavalent phosphate triester, said method comprising: (a) providing a 5' blocked-nucleoside; (b) deblocking the 5' blocked-nucleoside to form a 5' OH-nucleoside; (c) coupling the 5' OH-nucleoside with a phosphoramidite of formula (IV) wherein Y is 0, S, CH2, CHF, CF2 or--CH═CH--; bg is a 5'-blocking group; R'2 is H, OZ, a 2'-substituent, or together with R'4 forms a bridge; R'4 is H, OZ, a 2'-substituent, or together with R'2 forma a bridge; Z is H or a removable protecting group; Bx is a nucleobase; pg is a phosphorus protecting group; each G is 0 or S; L is an amine leaving group; G1 is 0 or S; and q' is 0 or 1; to form an oligonucleotide comprising a trivalent phosphite triester; and (d) oxidizing the oligonucleotide comprising a trivalent phosphite triester to form the oligonucleotide comprising a pentavalent phosphate triester; wherein at least a wash between any of the steps above is with a solvent wash comprising a toluene, pyridine, lutidine, hexane, cyclohexane, cyclohexene, a halogenated benzene, alkylated benzenes, a haloalkylbenzene, acetone, ethylacetate, methanol, ethanol, phenol, cyclic ethers, acyclic ethers, halogenated alkanes or mixtures thereof. 2. The method of claim 1, wherein a wash between any of the steps above is with at least one solvent wash comprising a toluene. 3. The method of claim 1, wherein the 5' blocked-nucleoside is linked to another nucleoside. 4. The method of claim 1, wherein the 5' blocked-nucleoside is linked to a solid support. 5. The method of claim 1 wherein the 5' blocked-nucleoside comprises a sugar moiety and a base. 6. The method of claim 1, wherein the solvent wash comprises a toluene and an acetonitrile. 7. The method of claim 1, wherein the solvent wash is substantially free of an acetonitrile. 8. A method of manufacturing a compound of Formula I: wherein Y is O, S, CH2, CHF, CF2 or--CH═CH--; bg is a 5'-blocking group; n is a positive integer; each R'2 is, independently, H, OZ, a 2'-substituent, or together with R'4 forms a bridge; each R'4 is, independently, H, OZ, a 2'-substituent, or together with R'4 forms a bridge; each R'4 is, protecting group; each Bx is independently a nucleobase; each pg is independently a phosphorus protecting group; each G is 0 or S; each G, is 0 or S; each q' is independently 0 or 1; and SS is a solid support; said process comprising: (a) contacting a compound of Formula II: with a deblocking agent to produce a compound of Formula III: (b) contacting the compound of Formula III with a first solvent wash; (c) contacting the compound of Formula III with a compound of Formula IV: wherein L is a leaving group, to form a compound of Formula V: (d) contacting the compound of Formula V with a second solvent wash; and (e) contacting the compound of Formula V with an oxidation reagent to form the compound of Formula I; wherein at least one of the first and second solvent wash comprises a toluene, pyridine, lutidine, hexane, cyclohexane, cyclohexene, a halogenated benzene, alkylated benzenes, a haloalkylbenzene, acetone, ethylacetate, methanol, ethanol, phenol, cyclic ethers, acyclic ethers, halogenated alkanes or mixtures thereof. 9. The method of claim 8, wherein the first solvent wash comprises the toluene. 10. The method of claim 8, wherein the first solvent wash comprises the toluene and an acetonitrile. 11. The method of claim 8, wherein the first solvent wash is substantially free of an acetonitrile. 12. The process according to claim 8, wherein the second solvent wash comprises a toluene. 13. The method of claim 8, wherein the second solvent wash comprises the toluene and an acetonitrile. 14. The method of claim 8, wherein the second solvent wash is substantially free of an acetonitrile. 15. The method of claim 8, after (e), further comprising: (f) contacting the compound of Formula I with a third solvent wash. 16. The method of claim 15, after (f), further comprising: (g) capping any compound of Formula III that has not reacted with the compound of Formula IV. 17. The method of claim 15, wherein the third solvent wash comprises at least one of a toluene, an acetonitrile, or mixture thereof. 18. The method of claim 15, wherein the third solvent wash is substantially free of an acetonitrile. 19. The method of claim 8, after (e), further comprising capping any compound of Formula IV that has not reacted with the compound of Formula IV. 20. The process according to claim 8, wherein each Y is 0. 21. The process of claim 8, wherein n is about 7 to about 79. 22. The process of claim 8, wherein each R'2 is H or a 2'-substituent. 23. The process of claim 8, wherein each R'2 is H or a 2'-substituent, said 2'-substituent being a member of the group consisting of 2'-O--CH3, 2'-O--CH2CH2OCH3, or 2'-O--(CH2)3NH2. 24. The process of claim 8, wherein said 2'-substituent is 2'-OCH2CH2OCH3. 25. The process of claim 8, wherein each q' is 1. 26. The process of claim 8, wherein each G is S. 27. A process of claim 8, further comprising cleaving the compound of Formula I from the solid support to form a compound of Formula X: wherein the variables have the same definitions as in claim 8.
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이 특허에 인용된 특허 (166)
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