N-acylphosphoramidites and their use in oligonucleotide synthesis
원문보기
IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
C07D-407/12
C07H-021/00
출원번호
US-0937292
(2000-02-16)
국제출원번호
PCT//US00/04032
(2002-01-25)
§371/§102 date
20020125
(20020125)
국제공개번호
WO00//56749
(2000-09-28)
발명자
/ 주소
Beaucage, Serge L.
Wilk, Andrzej
Grajkowski, Andrzej
출원인 / 주소
The United States of America as represented by the Department of Health and Human Services
대리인 / 주소
Leydig, Voit &
인용정보
피인용 횟수 :
1인용 특허 :
65
초록▼
The present invention provides a compound of formula (I), (II), or (III), wherein R1, R2, R2′, R3, and R3′ are the same or different and each is H an alkyl, an alkenyl, an alkynyl, a cycloalkyl, an aryl, or an aralkyl. Alternatively, either of R2 or R2′ combined with either of R3 or R3′ comprises a
The present invention provides a compound of formula (I), (II), or (III), wherein R1, R2, R2′, R3, and R3′ are the same or different and each is H an alkyl, an alkenyl, an alkynyl, a cycloalkyl, an aryl, or an aralkyl. Alternatively, either of R2 or R2′ combined with either of R3 or R3′ comprises a ring. R4 is a protecting group or a solid support R5 is H or an alkyl. R6 is a protecting group, an amidoalkyl, an alkyl, an alkyl ketone, an alkenyl, an alkynyl, a cycloalkyl, an aryl, or an aralkyl. R15 is H or a protecting group. Q and Q1 are the same or different and each is a nucleoside, an oligonucleotide comprising a nucleoside, or an oligomer comprising a nucleoside, which is of formula (a) or (b), wherein B is a labeling group, an alkyl, an alkenyl, an alkynyl, a cyclic group optionally containing one or more heteroatoms, or an amino; and, E is H, a halogen, a hydroxy, an alkoxy, an ester, an amino or a protecting group. X and X1 are independently O, S, or Se, and n is an integer from 1 to about 300. Each Q in each monomeric unit defined by n can be the same or different. The present invention further provides a method of preparing a polymer using the N-acylphosphoramidite of formula (I) or (II).
대표청구항▼
1. A compound of the formula: wherein:R1 is an alkyl, an alkenyl, an alkynyl, a cycloalkyl, an aryl, or an aralkyl, wherein R1 is unsubstituted or substituted with one or more substituents, which are the same or different selected from the group consisting of R7, OR7, SR7, NR8COR7, NR8CSR7, NR8CO2R7
1. A compound of the formula: wherein:R1 is an alkyl, an alkenyl, an alkynyl, a cycloalkyl, an aryl, or an aralkyl, wherein R1 is unsubstituted or substituted with one or more substituents, which are the same or different selected from the group consisting of R7, OR7, SR7, NR8COR7, NR8CSR7, NR8CO2R7, NR8C(O)SR7, NR8CS2R7, O2CR7, S2CR7, SCOR7, OCSR7, SO2R7, OSO2R7, NR8SO2R7, CN, NO2, N3, and a halogen, wherein R7 is an alkyl, an aryl or an aralkyl, wherein R7 is unsubstituted or substituted with one or more halogen atoms, which are the same or different, and R8 is H or an alkyl; R2 and R2′ are the same or different and each is H, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, an aryl, or an aralkyl, wherein R2 is unsubstituted or substituted with one or more substituents, which are the same or different, selected from the group consisting of OR7, CN, NO2, N3, and a halogen; R3 and R3′ are the same or different and each is H, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, an aryl, or an aralkyl, wherein R3 is unsubstituted or substituted with one or more substituents, which are the same or different, selected from the group consisting of a trialkylsilyl, an aryldialkylsilyl, an alkyldiarylsilyl, CN, NO2, N3, halogens, OR7, P(O)(OR7)(OR8), COR9, CSR9, CO2R9, COSR9, CSOR9, CONR8R9, CSNR8R9, SO2R9, and SO2NR8R9, wherein R9 is H, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, an aralkyl, or an aryl, wherein R9 is unsubstituted or substituted with one or more substituents, which are the same or different, selected from the group consisting of CN, NO2, N3, and a halogen; or R2 and R3, R2′ and R3, R2 and R3′, or R2′ and R3′, together with the carbon atoms to which they are bonded, form a cyclic substituent of the formula: wherein p is an integer from 0-6 and a-d are the same or different and each is selected from the group consisting of H, an alkyl, a nitro, an amino, a hydroxy, a thio, a cyano and a halogen;R4 is a protecting group or a solid support; Q is a nucleoside, an oligonucleotide having a nucleoside, or an oligomer having a nucleoside, wherein the nucleoside is of the formula: wherein:B is a labeling group, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, an aryl, a heteroaryl, a heterocycloalkyl, an aralkyl, an amino, an alkylamino, a dialkylamino, a purine, a pyrimidine, adenine, guanine, cytosine, uracil, or thymine, wherein B is unsubstituted or substituted with one or more substituents, which are the same or different, selected from the group consisting of a protecting group, R11, OR11, NHR11, NR11R12, CN, NO2, N3, and a halogen, wherein R11 and R12 are the same or different and each is H, a protecting group, or an alkyl; and, E is H, a halogen, OR13, NHR13, or NR13R14, wherein R13 and R14 are the same or different and each is H, a protecting group, an alkyl, or an acyl; and X is O, S, or Se, wherein the labeling group is a carboxyl to which is appended, via an amide linker, biotin, cholesterol, fluorenylmethoxycarbonyl (Fmoc), or trifluoroacetyl.2. The compound of claim 1, wherein Q is a nucleoside of the formula: wherein B and E are as defined in claim 1.3. The compound of claim 1, wherein the compound is of the formula: wherein R1-R4, B, and E are as defined in claim 1.4. The compound of claim 1, wherein Q is an oligonucleotide having a nucleoside, a nucleoside, or an oligomer having a nucleoside, wherein the nucleoside is of the formula: wherein B and E are as defined in claim 1.5. The compound of claim 4, wherein B is a purine, a pyrimidine, adenine, guanine, cytosine, uracil, or thymine, wherein B is unsubstituted or substituted with one or more substituents, which are the same or different, selected from the group consisting of a protecting group, R11, OR11, NHR11, NR11R12, CN, NO2, N3, and a halogen, wherein R11 and R12 are the same or different and each is H, a protecting group, or an alkyl.6. The compound of claim 1, wherein R1 is an alkyl, which is unsubstituted or substituted with one or more substituents, which are the same or different, selected from the group consisting of fluorine, OR7, and SR7, wherein R7 is an alkyl or an aryl.7. The compound of claim 6, wherein R3 is a vinyl group or a phenyl group.8. The compound of claim 1, wherein R4 is a 4,4′-dimethoxytrityl group.9. A method of preparing a polymer, the method comprising the steps of:(a) reacting a nucleophile of the formula R4?O?O?OH with the N-acylphosphoramidite of claim 1, wherein R4 and O are as defined in claim 1, to produce an adduct of the N-acylphosphoramidite and the nucleophile, the adduct comprising a tricoordinated phosphorus atom; (b) reacting the adduct with a reagent selected from the group consisting of oxidizing agents, sulfurizing agents, and selenizing agents, to produce a product, wherein the tricoordinated phosphorus atom is converted into a phosphorus atom with a valence of greater than three; (c) removing the protecting group R4 from the product; and (d) optionally repeating steps (a) through (c) one or more times until a polymer of specified length is obtained. 10. The method of claim 9, further comprising the step of cleaving the bond linking the organic moiety to the non-bridging phosphate, phosphorothioate or phosphoroselenoate oxygen atom in the product obtained in step (c) or (d).11. The method of claim 10, wherein the bond linking the organic moiety to the non-bridging phosphate, phosphorothioate or phosphoroselenoate oxygen atom is cleaved chemically.12. The method of claim 10, wherein the bond linking the organic moiety to the non-bridging phosphate, phosphorothioate or phosphoroselenoate oxygen atom is cleaved thermally.13. The method of claim 9, wherein the nucleophile is attached to a solid support.14. The method of claim 9, wherein the nucleophile is of the formula: wherein:Q is a nucleoside, oligonucleotide having a nucleoside, or an oligomer having a nucleoside, wherein the nucleoside is of the formula: wherein:B is a labeling group, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, an aryl, a heteroaryl, a heterocycloalkyl, an aralkyl, an amino, an alkylamino, a dialkylamino, a purine, a pyrimidine, adenine, guanine, cytosine, uracil, or thymine, wherein B is unsubstituted or substituted with one or more substituents, which are the same or different, selected from the group consisting of a protecting group, R11, OR11, NHR11, NR11R12, CN, NO2, N3, and a halogen, wherein R11 and R12 are the same or different and each is H, a protecting group, or an alkyl; and E is H, a halogen, OR13, NHR13, or NR13R14, wherein R13 and R14 are the same or different and each is H, a protecting group, an alkyl, or an acyl; and R4 is a solid support. 15. The method of claim 14, wherein Q is a nucleoside, an oligonucleotide having a nucleoside, or an oligomer having a nucleoside, wherein the nucleoside is of the formula: wherein B and E are as defined in claim 14.16. The method of claim 9, wherein the N-acylphosphoramidite is of the formula: wherein:R1 is an alkyl, an alkenyl, an alkynyl, a cycloalkyl, an aryl, or an aralkyl, wherein R1 is unsubstituted or substituted with one or more substituents, which are the same or different, selected from the group consisting of R7, OR7, SR7, NR8COR7, NR8CSR7, NR8CO2R7, NR8C(O)SR7, NR8CS2R7, O2CR7, S2CR7, SCOR7, OCSR7, SO2R7, OSO2R7, NR8SO2R7, CN, NO2, N3, and a halogen, wherein R7 is an alkyl, an aryl or an aralkyl, wherein R7 is unsubstituted or substituted with one or more halogen atoms, which are the same or different, and R8 is H or an alkyl; R2 is H, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, an aryl, or an aralkyl, wherein R2 is unsubstituted or substituted with one or more substituents, which are the same or different, selected from the group consisting of OR7, CN, NO2, N3, and a halogen; R3 is H, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, an aryl, or an aralkyl, wherein R3 is unsubstituted or substituted with one or more substituents, which are the same or different, selected from the group consisting of a trialkylsilyl, an aryldialkylsilyl, an alkyldiarylsilyl, CN, NO2, N3, a halogen, OR7, P(O)(OR7)(OR8), COR9, CSR9, CO2R9, COSR9, CSOR9, CONR8R9, CSNR8R9, SO2R9, and SO2NR8R9, wherein R9 is H, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, an aralkyl, or an aryl, wherein R9 is unsubstituted or substituted with one or more substituents, which are the same or different, selected from the group consisting of CN, NO2, N3, and a halogen; or R2 and R3, together with the carbon atoms to which they are bonded, form a cyclic substituent of the formula: wherein p is an integer from 0-6 and a-d are the same or different and each is selected from the group consisting of H, an alkyl, a nitro, an amino, a hydroxy, a thio, a cyano and a halogen;R4 is a protecting group or a solid support; B is a labeling group, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, an aryl, a heteroaryl, a heterocycloalkyl, an aralkyl, an amino, an alkylamino, a dialkylamino, a purine, a pyrimidine, adenine, guanine, cytosine, uracil, or thymine, wherein B is unsubstituted or substituted with one or more substituents, which are the same or different, selected from the group consisting of a protecting group, R11, OR11, NHR11, NR11R12, CN, NO2, N3, and a halogen, wherein R11 and R12 are the same or different and each is H, a protecting group, or an alkyl; and, E is H, a halogen, OR13, NHR13, or NR13R14, wherein R13 and R14 are the same or different and each is H, a protecting group, an alkyl, or an acyl. 17. The method of claim 16, wherein B is a purine, a pyrimidine, adenine, guanine, cytosine, uracil, or thymine, wherein B is unsubstituted or substituted with one or more substituents, which are the same or different, selected from the group consisting of a protecting group, R11, OR11, NHR11, NR11R12, CN, NO2, N3, and a halogen, wherein R11 and R12 are the same or different and each is H, a protecting group, or an alkyl.18. The method of claim 16, wherein R1 is an alkyl, which is unsubstituted or substituted with one or more substituents, which are the same or different, selected from the group consisting of fluorine, OR7, and SR7, wherein R7 is an alkyl, an aryl, or an aralkyl.19. The method of claim 16, wherein R3 is a vinyl group, a phenyl, or a benzyl.20. The method of claim 16, wherein R4 is a 4,4′-dimethoxytrityl.
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이 특허에 인용된 특허 (65)
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