IPC분류정보
국가/구분 |
United States(US) Patent
등록
|
국제특허분류(IPC7판) |
|
출원번호 |
UP-0556219
(2004-05-07)
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등록번호 |
US-7612197
(2009-11-16)
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국제출원번호 |
PCT/US04/014185
(2004-05-07)
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§371/§102 date |
20051109
(20051109)
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국제공개번호 |
WO04/101582
(2004-11-25)
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발명자
/ 주소 |
- Beaucage, Serge L
- Chmielewski, Marcin K
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출원인 / 주소 |
- The United States of America as repesented by the Secretary of the Department of Health and Human Services
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대리인 / 주소 |
Leydig, Voit & Mayer, Ltd.
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인용정보 |
피인용 횟수 :
1 인용 특허 :
9 |
초록
▼
Provided is a hydroxyl-protected alcohol comprising a thermolabile hydroxyl-protecting group comprising a 2-pyridyl substituent and a precursor of the thermolabile hydroxyl-protected alcohol. An exemplary thermolabile hydroxyl-protected alcohol is represented by the formula Pg-O--R, wherein Pg is a
Provided is a hydroxyl-protected alcohol comprising a thermolabile hydroxyl-protecting group comprising a 2-pyridyl substituent and a precursor of the thermolabile hydroxyl-protected alcohol. An exemplary thermolabile hydroxyl-protected alcohol is represented by the formula Pg-O--R, wherein Pg is a protecting group of the formula: (Formula) wherein: A is a 2-pyridyl; Z is CH2 or NR1; R1, R2, R2', R3 and R3' are the same or different and each can be, e.g., H, alkyl, or alkyl comprising an aryl substituent; W is CO, CS, or SO; and R is the organic residue of the hydroxyl-protected alcohol. Also provided is a method of producing an alcohol, which method comprises heating the hydroxyl-protected alcohol, which optionally may be obtained from a precursor, at a temperature effective to cleave the hydroxyl-protecting group. The method can be used to produce oligonucleotides.
대표청구항
▼
What is claimed is: 1. A hydroxyl-protected alcohol of the formula Pg-O--R, wherein Pg is a protecting group of the formula: wherein: A is a 2-pyridyl group of the formula: Z is CH2 or NR1; R1, R2, R2', R3 and R3' are the same or different and each is H, a saturated alkyl, an unsaturated alky
What is claimed is: 1. A hydroxyl-protected alcohol of the formula Pg-O--R, wherein Pg is a protecting group of the formula: wherein: A is a 2-pyridyl group of the formula: Z is CH2 or NR1; R1, R2, R2', R3 and R3' are the same or different and each is H, a saturated alkyl, an unsaturated alkyl, an aryl, a saturated alkyl comprising an aryl substituent, or an unsaturated alkyl comprising an aryl substituent, wherein the saturated alkyl, unsaturated alkyl and aryl portions are optionally substituted; R4, R5, R6, and R7 are the same or different and each is H, an amino, a monoalkylamino, a dialkylamino, a hydroxy, an alkoxy, a halogen, an amide, a saturated alkyl, an unsaturated alkyl, an aryl, a saturated alkyl comprising an aryl, or an unsaturated alkyl comprising an aryl; W is CO; and R is a nucleoside, an oligonucleotide, or an oligomer comprising a nucleoside, wherein the protecting group is thermolabile. 2. The hydroxyl-protected alcohol of claim 1, wherein Z is NR1. 3. The hydroxyl-protected alcohol of claim 2, wherein R1 is H or a saturated alkyl. 4. The hydroxyl-protected alcohol of claim 1, wherein, when R1, R2, R2', R3 or R3'is a saturated alkyl, an unsaturated alkyl, a saturated alkyl comprising an aryl substituent, or an unsaturated alkyl comprising an aryl substituent, the unsaturated alkyl or saturated alkyl is unsubstituted or substituted with one or more substituents, which are the same or different, selected from the group consisting of a halogen, a saturated alkyl, an unsaturated alkyl, a hydroxyl, an alkoxy, an aryloxy, an aralkoxy, an ester, an amide, a sulfhydryl, an alkyl sulfide, an aryl sulfide, an alkyl sulfoxide, an aryl sulfoxide, an alkyl sulfonyl, an aryl sulfonyl, a keto, a thioketo, a cyano, and a nitro. 5. The hydroxyl-protected alcohol of claim 1, wherein Pg is selected from the group consisting of: 6. A hydroxyl-protected alcohol of the formula Pg-O--R, wherein Pg is a protecting group of the formula: wherein: A is a 2-pyridyl group of the formula: Z is CH2 or NR1; R1, R2, R2', R3 and R3' are the same or different and each is H, a saturated alkyl, an unsaturated alkyl, an aryl, a saturated alkyl comprising an aryl substituent, or an unsaturated alkyl comprising an aryl substituent, wherein the saturated alkyl, unsaturated alkyl and aryl portions are optionally substituted; R4, R5, R6, and R7 are the same or different and each is H, an amino, a monoalkylamino, a dialkylamino, a hydroxy, an alkoxy, a halogen, an amide, a saturated alkyl, an unsaturated alkyl, an aryl, a saturated alkyl comprising an aryl, or an unsaturated alkyl comprising an aryl; W is CO; and R is the organic residue of the hydroxyl-protected alcohol of the formula: wherein: Q is a nucleoside, an oligonucleotide, or an oligomer comprising a nucleoside; X is O, S or Se; R8 is H, a protecting group or a solid support; R9 is H or a protecting group; B is a labeling group, a saturated alkyl, an unsaturated alkyl, a cycloalkyl, an aryl, a heteroaryl comprising from 5 to about 10 atoms in the ring skeleton thereof, a heterocycloalkyl comprising from 3 to about 10 atoms in the ring skeleton thereof, a saturated alkyl comprising an aryl substituent, an unsaturated alkyl comprising an aryl substituent, 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 nucleobase protecting group, R10, OR10, NHR10, NR10R11, N═CH--NR10aR11a, N═C(alkyl)-NR10aR11a, CN, NO2, N3, and a halogen, wherein R10 and R11 are the same or different and each is H, a saturated alkyl, an unsaturated alkyl, a keto, or a thioketo, and R10a and R11 are the same or different and each is a saturated alkyl or an unsaturated alkyl, or, R10a and R11a, together with the nitrogen atom to which they are bonded, form a heterocycle containing 3 to about 7 atoms in the ring skeleton thereof; and E is H, a halogen, OR12, NHR12, or NR12R13, wherein R12 and R13 are the same or different and each is H, a protecting group, a saturated alkyl, an unsaturated alkyl, a keto or a thioketo; wherein the protecting group is thermolabile. 7. A method of producing an alcohol, the method comprising heating the hydroxyl-protected alcohol of claim 1, so as to deprotect the hydroxyl-protected alcohol, whereupon an alcohol is produced. 8. The method of claim 7, wherein A is 2-pyridyl or 2-pyridyl having an amino substituent. 9. The method of claim 8, wherein the hydroxyl-protected alcohol is provided by reducing a precursor of the formula: wherein A' is a 2-pyridyl comprising a nitro-substituent, a 2-pyridyl-1-oxide, or a 2-pyridyl-1-oxide comprising a nitro substituent; Z is CH2 or NR1, R1, R2, R2', R3 and R3' are the same or different and each is H, a saturated alkyl, an unsaturated alkyl, an aryl, a saturated alkyl comprising an aryl substituent, or an unsaturated alkyl comprising an aryl substituent, wherein the saturated alkyl, unsaturated alkyl and aryl portions are optionally substituted; W is CO; and R is the organic residue of the hydroxyl-protected alcohol, so as to produce the hydroxyl-protected alcohol. 10. The method of claim 9, wherein A' is selected from the group consisting of 11. The method of claim 9, wherein, when R1, R2, R2', R3 or R3'is a saturated alkyl, an unsaturated alkyl, a saturated alkyl comprising an aryl substituent, or an unsaturated alkyl comprising an aryl substituent, the unsaturated alkyl or saturated alkyl is unsubstituted or substituted with one or more substituents, which are the same or different, selected from the group consisting of a halogen, a saturated alkyl, an unsaturated alkyl, a hydroxy, an alkoxy, an aryloxy, an aralkoxy, an ester, an amide, a sulfhydryl, an alkyl sulfide, an aryl sulfide, an alkyl sulfoxide, an aryl sulfoxide, an alkyl sulfonyl, an aryl sulfonyl, a keto, a thioketo, a cyano, and a nitro. 12. The method of claim 9, wherein the precursor is of the formula: 13. The method of claim 7, wherein the hydroxyl-protected alcohol is a 2-(2-pyridyl)aminoethoxycarbonyl protected alcohol. 14. The method of claim 13, wherein the protecting group is selected from the group consisting of: 15. A method of producing an oligonucleotide, the method comprising: (a) reacting a nucleophile with an electrophile to produce an adduct of the formula: (b) reacting the adduct obtained in step (a) with a reagent selected from the group consisting of oxidizing agents, sulfurizing agents, and selenizing agents to produce a hydroxyl-protected oligonucleotide of the formula: (c) thermally cleaving Pg to produce a nucleophile of the formula; (d) optionally repeating steps (a)-(c) to produce an oligomer of the formula: (e) optionally removing R14; and (f) optionally removing R15; wherein: Pg is a thermolabile hydroxyl-protecting group as defined in claim 1; n is an integer from 2 to about 300; R14 is a protecting group or a solid support; R15 R is a protecting group; Q and Q' are the same or different and each is a nucleoside, an oligonucleotide, or an oligomer comprising a nucleoside; and X is O, S or Se. 16. An alcohol protected with a hydroxyl-protecting group selected from the group consisting of a 2-(2-pyridyl)aminoethoxycarbonyl and a 3-(2-pyridyl) propoxycarbonyl, wherein the alcohol is a nucleoside, an oligonucleotide, or an oligomer comprising a nucleoside. 17. An alcohol protected with a hydroxyl-protecting group selected from the group consisting of a 2-(substituted-2-pyridyl)aminoethoxycarbonyl and a 3-(substituted-2-pyridyl) propoxycarbonyl, wherein the 2-pyridyl ring is substituted with a nitro substituent, a 1-oxide substituent, or a nitro substituent and a 1-oxide substituent. 18. The hydroxyl-protected alcohol of claim 2, wherein R1 is methyl. 19. The hydroxyl-protected alcohol of claim 1, wherein, when R1, R2, R2', R3 or R3' is an aryl, a saturated alkyl comprising an aryl substituent, or an unsaturated alkyl comprising an aryl substituent, the aryl or aryl substituent is unsubstituted or substituted with one or more substituents, which are the same or different, selected from the group consisting of a halogen, a saturated alkyl, an unsaturated alkyl, a hydroxy, an alkoxy, an aryloxy, an aralkoxy, an ester, an amide, a sulfhydryl, an alkyl sulfide, an aryl sulfide, an alkyl sufoxide, an aryl sulfoxide, an alkylsulfonyl, an arylsulfonyl, a keto, a thioketo, a cyano, a nitro, an amino, a monoalkylamino, and a dialkylamino. 20. The hydroxyl-protected alcohol of claim 1, wherein, when R1, R2, R2', R3 or R3' is a saturated alkyl, an unsaturated alkyl, a saturated alkyl comprising an aryl substituent, or an unsaturated alkyl comprising an aryl substituent, the unsaturated alkyl or saturated alkyl is unsubstituted or substituted with one or more substituents, which are the same or different, selected from the group consisting of a halogen, a saturated alkyl, an unsaturated alkyl, a hydroxyl, an alkoxy, an aryloxy, an aralkoxy, an ester, an amide, a sulfhydryl, an alkyl sulfide, an aryl sulfide, an alkyl sulfoxide, an aryl sulfoxide, an alkyl sulfonyl, an aryl sulfonyl, a cyano, and a nitro. 21. The hydroxyl-protected alcohol of claim 1, wherein, when R1, R2, R2', R3 or R3' is an aryl, a saturated alkyl comprising an aryl substituent, or an unsaturated alkyl comprising an aryl substituent, the aryl or aryl substituent is unsubstituted or substituted with one or more substituents, which are the same or different, selected from the group consisting of a halogen, a saturated alkyl, an unsaturated alkyl, a hydroxy, an alkoxy, an aryloxy, an aralkoxy, an ester, an amide, a sulfhydryl, an alkyl sulfide, an aryl sulfide, an alkyl sufoxide, an aryl sulfoxide, an alkylsulfonyl, an arylsulfonyl, a cyano, a nitro, an amino, a monoalkylamino, and a dialkylamino. 22. The hydroxyl-protected alcohol of claim 1, wherein R2 and R2' are H. 23. The hydroxyl-protected alcohol of claim 1, wherein R3 and R3' are H. 24. The hydroxyl-protected alcohol of claim 1, wherein one of R3 and R3' is H and the other is an aryl. 25. The hydroxyl-protected alcohol of claim 1, wherein, when R1, R2, R2', R3 or R3' is an unsaturated alkyl or an unsaturated alkyl comprising an aryl substituent, the unsaturated alkyl is an alkenyl or an alkynyl. 26. A hydroxyl-protected alcohol of the formula Pg-O--R, wherein Pg is a protecting group of the formula: wherein: A is a 2-pyridyl group of the formula: Z is CH2 or NR1; R1, R2, R2', R3 and R3' are the same or different and each is H, a saturated alkyl, an unsaturated alkyl, an aryl, a saturated alkyl comprising an aryl substituent, or an unsaturated alkyl comprising an aryl substituent, wherein the saturated alkyl, unsaturated alkyl and aryl portions are optionally substituted; R4, R5, R6, and R7 are the same or different and each is H, an amino, a monoalkylamino, a dialkylamino, a hydroxy, an alkoxy, a halogen, an amide, a saturated alkyl, an unsaturated alkyl, an aryl, a saturated alkyl comprising an aryl, or an unsaturated alkyl comprising an aryl; W is CO; and R is the organic residue of the hydroxyl-protected alcohol, wherein when Z is CH2, at least one of R2, R2', R3, R3', R4, R5, R6, and R7 is not H, and wherein the protecting group is thermolabile. 27. A hydroxyl-protected alcohol of the formula Pg-O--R, wherein Pg is a protecting group of the formula: wherein: A is a 2-pyridyl group of the formula: Z is CH2 or NR1; R1, R2, R2', R3 and R3' are the same or different and each is H, a saturated alkyl, an unsaturated alkyl, an aryl, a saturated alkyl comprising an aryl substituent, or an unsaturated alkyl comprising an aryl substituent, wherein the saturated alkyl, unsaturated alkyl and aryl portions are optionally substituted; R4, R5, R6, and R7 are the same or different and each is H, an amino, a monoalkylamino, a dialkylamino, a hydroxy, an alkoxy, a halogen, an amide, a saturated alkyl, an unsaturated alkyl, an aryl, a saturated alkyl comprising an aryl, or an unsaturated alkyl comprising an aryl; W is CO; and R is the organic residue of the hydroxyl-protected alcohol, wherein R is not a low molecular weight aromatic alcohol, and wherein the protecting group is thermolabile.
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