US2007232798A1PendingUtilityA1
Process For The Synthesis Of 2'-O-Substituted Pyrimidines And Oligomeric Compounds Therefrom
Individually held — no corporate assignee on recordPriority: Mar 6, 1995Filed: Mar 12, 2007Published: Oct 4, 2007
Est. expiryMar 6, 2015(expired)· nominal 20-yr term from priority
Inventors:Phillip Dan CookYogesh S. SanghviKelly G. SprankleBruce RossRich GriffeyRobert H. Springer
Y02P20/55C07H 21/00A61P 35/00Y02P20/582A61P 37/04A61P 31/18C07H 19/06A61P 31/12
57
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Claims
Abstract
Oligonucleotide analogs are disclosed having pyrimidine monomeric sub-units therein that are modified at the 2′ and 5′ positions. Monomeric sub-units having these modifications may be further modified at the 2′ position. Improved processes for the synthesis of 2′-O-substituted pyrimidine nucleosides are also provided. The processes feature alkylation of a 2,2′-anhydropyrimidine nucleoside or a 2S,2′-anhydropyrimidine nucleoside with a weak nucleophile in the presence of a Lewis acid.
Claims
exact text as granted — not AI-modified1 . An oligomeric compound comprising at least one monomeric sub-unit of structure I:
wherein:
X is hydroxyl or amino;
R is halo or C 1 -C 6 alkyl or substituted C 1 -C 6 alkyl wherein said substitution is halo, amino, hydroxyl, thiol, ether or thioether;
L is oxygen or sulfur;
Z is fluoro or O—R 1 X 1 , where R 1 is C 1 -C 6 alkyl, C 6 -C 10 aryl, C 7 -C 18 alkaryl and X 1 is H, NH 2 or imidazole; and
one of Q 1 and Q 2 is attached via a linking moiety to a nucleotide, oligonucleotide, nucleoside, or oligonucleoside and the other of said Q 1 and Q 2 , is a hydroxyl, a protected hydroxyl, an activated solid support, a nucleotide, an oligonucleotide, a nucleoside, an oligonucleoside, an oligo-nucleotide/nucleoside, an activated phosphate, a phosphate, an activated phosphite, or a phosphite.
2 . The oligomeric compound of claim 1 , wherein L is O.
3 . The oligomeric compound of claim 1 , wherein Z is F.
4 . The oligomeric compound of claim 1 , comprising from 5 to 200 sub-units.
5 . The oligomeric compound of claim 1 , comprising from 5 to 50 sub-units.
6 . The oligomeric compound of claim 1 , comprising from 10 to 20 sub-units.
7 . The oligomeric compound of claim 1 , wherein said linking moiety comprises a phosphodiester, phosphotriester, hydrogen phosphonate, alkylphosphonate, alkylphosphonothioate, arylphosphonothioate, phosphorothioate, phosphorodithioate, or phosphoramidate.
8 . The oligomeric compound of claim 1 having a plurality of monomeric sub-units of structure I.
9 . The oligomeric compound of claim 8 wherein said monomeric sub-units are located at preselected positions.
10 . An oligomeric compound comprising at least one monomeric sub-unit of structure II:
wherein:
X is hydroxyl or amino;
R is halo or C 1 -C 6 alkyl or substituted C 1 -C 6 alkyl wherein said substitution is halo, amino, hydroxyl, thiol, ether or thioether;
L is oxygen or sulfur; and
one of Q 1 and Q 2 is attached via a linking moiety to a nucleotide, oligonucleotide, nucleoside, or oligonucleoside and the other of said Q 1 and Q 2 , is a hydroxyl, a protected hydroxyl, an activated solid support, a nucleotide, an oligonucleotide, a nucleoside, an oligonucleoside, an oligo-nucleotide/nucleoside, an activated phosphate, a phosphate, an activated phosphite, or a phosphite.
11 . The oligomeric compound of claim 10 , wherein L is O.
12 . The oligomeric compound of claim 10 , comprising from 5 to 50 sub-units.
13 . The oligomeric compound of claim 10 , comprising from 10 to 20 sub-units.
14 . The oligomeric compound of claim 10 , wherein said linking moiety comprises a phosphodiester, phosphotriester, hydrogen phosphonate, alkylphosphonate, alkylphosphonothioate, arylphosphonothioate, phosphorothioate, phosphorodithioate, or phosphoramidate.
15 . The oligomeric compound of claim 10 having a plurality of monomeric sub-units of structure II.
16 . The oligomeric compound of claim 15 wherein said monomeric sub-units are located at preselected positions.
17 . An oligomeric compound comprising at least one monomeric sub-unit of structure III:
wherein:
X is hydroxyl or amino;
R is halo or C 1 -C 6 alkyl or substituted C 1 -C 6 alkyl wherein said substitution is halo, amino, hydroxyl, thiol, ether or thioether;
L is oxygen or sulfur;
R 1 is C 1 -C 6 alkyl, C 6 -C 10 aryl, C 7 -C 18 alkaryl and X 1 is H, NH 2 or imidazole; and
one of Q 1 and Q 2 is attached via a linking moiety to a nucleotide, oligonucleotide, nucleoside, or oligonucleoside and the other of said Q 1 and Q 2 , is a hydroxyl, a protected hydroxyl, an activated solid support, a nucleotide, an oligonucleotide, a nucleoside, an oligonucleoside, an oligo-nucleotide/nucleoside, an activated phosphate, a phosphate, an activated phosphite, or a phosphite.
18 . The oligomeric compound of claim 17 , wherein L is O.
19 . The oligomeric compound of claim 17 , comprising from 5 to 50 sub-units.
20 . The oligomeric compound of claim 17 , comprising from 5 to 50 sub-units.
21 . The oligomeric compound of claim 17 , wherein said linking moiety comprises a phosphodiester, phosphotriester, hydrogen phosphonate, alkylphosphonate, alkylphosphonothioate, arylphosphonothioate, phosphorothioate, phosphorodithioate, or phosphoramidate.
22 . The oligomeric compound of claim 17 having a plurality of monomeric sub-units of structure I.
23 . The oligomeric compound of claim 22 wherein said monomeric sub-units are located at preselected positions.
24 . A process for the synthesis of a 2′-O-substituted pyrimidine nucleoside of formula:
wherein:
Q is a pyrimidine base or a 2-S pyrimidine base;
R 1 is substituted or unsubstituted C 1 -C 30 alkyl, C 1 -C 30 alkenyl, C 1 -C 30 alkynyl, C 6 -C 14 aryl, or C 7 -C 30 aralkyl, wherein said substitution is halo, amino, hydroxyl, thiol, ether or thioether; and
R 2 and R 3 are independently hydrogen or a hydroxyl protecting group;
comprising the steps of:
providing a 2-2′-anhydropyrimidine nucleoside;
selecting an alcohol of the formula R 1 —OH; and
treating said 2-2′-anhydropyrimidine nucleoside and said alcohol with a Lewis acid under conditions of time, temperature and pressure effective to yield said 2′-O-substituted pyrimidine nucleoside.
25 . The process of claim 24 wherein said 2-2′-anhydropyrimidine nucleoside and said alcohol are treated in a pressure sealed vessel.
26 . The process of claim 24 wherein said Lewis acid is a borate.
27 . The process of claim 26 wherein said borate is a trialkyl borate.
28 . The process of claim 27 wherein the formula of said trialkyl borate is B(OR 1 ) 3 .
29 . The process of claim 28 wherein said trialkyl borate is prepared from the treatment of borane with an alcohol.
30 . The process of claim 29 wherein said trialkyl borate is prepared from the treatment of borane with an alcohol of formula HO—R 1 .
31 . The process of claim 24 wherein R 1 is C 1 -C 10 alkyl.
32 . The process of claim 24 wherein R 1 is C 6 -C 14 aryl.
33 . The process of claim 24 wherein said treating comprises heating at from about 120° C. to about 200° C.
34 . The process of claim 24 wherein said pyrimidine nucleoside is uridine or 5-methyluridine.
35 . A process for the synthesis of a 2′-O-substituted cytidine nucleoside of formula:
wherein:
X′ is O or S;
R 1 is substituted or unsubstituted C 1 -C 30 alkyl, C 1 -C 30 alkenyl, C 1 -C 30 alkynyl, C 6 -C 14 aryl, or C 7 -C 30 aralkyl, wherein said substitution is halo, amino, hydroxyl, thiol, ether or thioether;
R 2 and R 3 are independently hydrogen or a hydroxyl protecting group;
R 5 and R 6 are independently H, C 1 -C 30 hydrocarbyl or substituted C 1 -C 30 hydrocarbyl;
comprising the steps of:
providing a 2-2′-anhydrouridine nucleoside of formula:
selecting an alcohol of formula R 1 —OH;
treating said 2-2′-anhydrouridine nucleoside and said alcohol with a Lewis acid under conditions of time, temperature and pressure effective to form a 2′—O— substituted uridine nucleoside; and
aminating said 2′-O-substituted uridine nucleoside to said 2′-O-substituted cytidine nucleoside.
36 . The process of claim 35 wherein said 2-2′-anhydrouridine nucleoside and said alcohol are treated in a pressure sealed vessel.
37 . The process of claim 35 wherein said Lewis acid is a borate.
38 . The process of claim 37 wherein said borate is a trialkyl borate.
39 . The process of claim 38 wherein the formula of said trialkyl borate is B(OR 1 ) 3 .
40 . The process of claim 38 wherein said trialkyl borate is prepared from the treatment of borane with an alcohol.
41 . The process of claim 40 wherein said trialkyl borate is prepared from the treatment of borane with an alcohol of formula HO—R 1 .
42 . The process of claim 35 wherein R 1 is C 1 -C 10 alkyl.
43 . The process of claim 35 wherein R 1 is C 6 -C 14 aryl.
44 . The process of claim 35 wherein said treating comprises heating from about 120° C. to about 200° C.
45 . The process of claim 35 wherein said 2′-O-substituted cytidine nucleoside is 2′-O-methyl-S-methylcytidine.
46 . An oligomeric compound comprising at least one monomeric sub-unit of formula:
wherein:
A is hydroxyl or amino;
R is halo or C 1 -C 6 alkyl or substituted C 1 -C 6 alkyl wherein said substitution is halo, amino, hydroxyl, thiol, ether or thioether;
L is oxygen or sulfur;
Z′ is substituted or unsubstituted C 1 -C 30 alkyl, C 1 -C 30 alkenyl, C 1 -C 30 alkynyl, C 6 -C 14 aryl, or C 7 -C 30 aralkyl, wherein said substitution is halo, amino, hydroxyl, thiol, ether or thioether; and
one of Q 1 and Q 2 is attached via a linking moiety to a nucleotide, oligonucleotide, nucleoside, or oligonucleoside and the other of said Q 1 and Q 2 , is a hydroxyl, a protected hydroxyl, an activated solid support, a nucleotide, an oligonucleotide, a nucleoside, an oligonucleoside, an oligo-nucleotide/nucleoside, an activated phosphate, a phosphate, an activated phosphite, or a phosphite.
47 . The oligomeric compound of claim 46 , wherein L is O.
48 . The oligomeric compound of claim 46 , wherein Z is —(CH 2 ) n —O—(CH 2 ) n —CH 3 .
49 . The oligomeric compound of claim 48 , wherein n is 2 and m is 0.
50 . The oligomeric compound of claim 46 , comprising from 5 to 200 sub-units.
51 . The oligomeric compound of claim 46 , comprising from 5 to 50 sub-units.
52 . The oligomeric compound of claim 46 , comprising from 10 to 20 sub-units.
53 . The oligomeric compound of claim 46 , wherein said linking moiety comprises a phosphodiester, phosphotriester, hydrogen phosphonate, alkylphosphonate, alkylphosphonothioate, arylphosphonothioate, phosphorothioate, phosphorodithioate, or phosphoramidate.
54 . The oligomeric compound of claim 46 having a plurality of monomeric sub-units of said formula.
55 . The oligomeric compound of claim 54 wherein said monomeric sub-units are located at preselected positions.Join the waitlist — get patent alerts
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