US2023136645A1PendingUtilityA1
Compositions and methods for phosphoramidite and oligonucleotide synthesis
Est. expiryMar 13, 2036(~9.7 yrs left)· nominal 20-yr term from priority
C07H 1/06C07H 19/16C07H 19/06C07F 9/65844C07H 19/173C07H 19/073C07H 23/00C07D 413/12C07D 417/14C07D 471/04C07D 405/14
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Claims
Abstract
The present disclosure, among other things, provides technologies for preparing and purifying phosphoramidites for oligonucleotide synthesis.
Claims
exact text as granted — not AI-modified1 - 15 . (canceled)
16 . A composition comprising:
a) a pre-treated purification medium; and b) a phosphoramidite; or
a composition comprising:
a) silica gel pre-treated with a hygroscopic solvent; and
b) a phosphoramidite:
wherein:
the phosphoramidite has the structure of formula I,
wherein:
BA is R, or an optionally substituted group selected from a 3-30 membered cycloaliphatic ring, a 6-30 membered aryl ring, a 3-30 membered heterocyclyl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, a 5-30 membered heteroaryl ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, a natural nucleobase moiety and a modified nucleobase moiety;
SU is a sugar moiety, a modified sugar moiety, -L-O— or
wherein SU is connected to the phosphorus atom in formula I through the oxygen atom;
L is a covalent bond, or a bivalent, optionally substituted, linear or branched group selected from C 1-30 aliphatic and C 1-30 heteroaliphatic group having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, wherein one or more methylene units are optionally and independently replaced by an optionally substituted C 1-6 alkylene, C 1-6 alkenylene, —C≡C—, —C(R′) 2 —, -Cy-, —O—, —S—, —S—S—, —N(R′)—, —C(O)—, —C(S)—, —C(NR′)—, —C(O)N(R′)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)—, —N(R′)C(O)O—, —OC(O)N(R′)—, —S(O)—, —S(O) 2 —, —S(O) 2 N(R′)—, —N(R′)S(O) 2 —, —SC(O)—, —C(O)S—, —OC(O)—, or —C(O)O—;
R 5s is R′ or —OR′;
R 2s is —F, —CN, —N 3 , —NO, —NO 2 , -R′, —OR′, —SR′, —N(R′) 2 , -L-R′, —O-L-OR′, —O-L-SR′, or —O-L-N(R′) 2 , or R 2s is L connecting C2 with C1, C2, C3, C4 or C5;
-Cy- is an optionally substituted bivalent ring selected from 3-30 membered carbocyclylene, 6-30 membered arylene, 5-30 membered heteroarylene having 1-10 heteroatoms independently selected from oxygen, nitrogen and sulfur, and 3-30 membered heterocyclylene having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon;
R 1 , R 2 , and R 3 are taken together with their intervening atoms to form:
Ring A is an optionally substituted multivalent, monocyclic, bicyclic or polycyclic, saturated, partially unsaturated, or aryl 3-30 membered ring having, in addition to the intervening atoms, 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon;
each R s is independently R′ or -L-R′;
t is 0-5;
each R′ is independently —R, —C(O)R, —CO 2 R, or —SO 2 R, or:
two or more R′ are taken together with their intervening atoms to form an optionally substituted monocyclic, bicyclic or polycyclic, saturated, partially unsaturated, or aryl 3-30 membered ring having, in addition to the intervening atoms, 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon; and
each R is independently hydrogen, or an optionally substituted group selected from C 1-30 aliphatic, C 1-30 heteroaliphatic having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, a 6-30 membered aryl ring, a 5-30 membered heteroaryl ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, and a 3-30 membered heterocyclic ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon.
17 - 19 . (canceled)
20 . The composition of claim 16 , wherein the composition comprising:
a) a pre-treated purification medium; and b) a phosphoramidite.
21 . The composition of claim 16 , wherein BA is a natural nucleobase moiety and a modified nucleobase moiety.
22 . The composition of claim 3 , wherein SU is
23 . The composition of claim 22 , wherein R 5s is —ODMTr.
24 . The composition of claim 22 , wherein R 2s is selected form —H, —F, —OMe, and —OCH 2 CH 2 OMe.
25 . The composition of claim 16 , wherein
wherein one or more R 5s is not hydrogen.
26 . The method of claim 16 , wherein
27 . The composition of claim 16 , wherein
28 . The composition of claim 16 , wherein the phosphoramidite is selected from:
or is selected from:
wherein X is
and:
R′ is H and R is H,
R′ is H, R is OMe,
R′ is H and R is OCH 2 CH 2 OMe,
R′ is H and R is F,
R′ is Me and R is H,
R′ is Me, R is OMe,
R′ is Me and R is OCH 2 CH 2 OMe, or
R′ is Me and R is F;
wherein X is
and
R′ is H and R is H,
R′ is H, R is OMe,
R′ is H and R is OCH 2 CH 2 OMe,
R′ is H and R is F,
R′ is Me and R is H,
R′ is Me, R is OMe,
R′ is Me and R is OCH 2 CH 2 OMe, or
R′ is Me and R is F;
wherein X is
and:
R′ is H and R is H,
R′ is H, R is OMe,
R′ is H and R is OCH 2 CH 2 OMe,
R′ is H and R is F,
R′ is Me and R is H,
R′ is Me, R is OMe,
R′ is Me and R is OCH 2 CH 2 OMe, or
R′ is Me and R is F;
wherein X is
and
R′ is H and R is H,
R′ is H, R is OMe,
R′ is H and R is OCH 2 CH 2 OMe,
R′ is H and R is F,
R′ is Me and R is H,
R′ is Me, R is OMe,
R′ is Me and R is OCH 2 CH 2 OMe, or
R′ is Me and R is F;
wherein X is
and:
R′ is Ac and R is H,
R′ is Ac, R is OMe,
R′ is Ac and R is OCH 2 CH 2 OMe,
R′ is Ac and R is F,
R′ is iBu and R is H,
R′ is iBu, R is OMe,
R′ is iBu and R is OCH 2 CH 2 OMe, or
R′ is iBu and R is F;
wherein X is
and:
R′ is Ac and R is H,
R′ is Ac, R is OMe,
R′ is Ac and R is OCH 2 CH 2 OMe,
R′ is Ac and R is F,
R′ is iBu and R is H,
R′ is iBu, R is OMe,
R′ is iBu and R is OCH 2 CH 2 OMe, or
R′ is iBu and R is F;
wherein X is
and:
R′ is Ac and R is H,
R′ is Ac, R is OMe,
R′ is Ac and R is OCH 2 CH 2 OMe,
R′ is Ac and R is F,
R′ is iBu and R is H,
R′ is iBu, R is OMe,
R′ is iBu and R is OCH 2 CH 2 OMe, or
R′ is iBu and R is F;
wherein X is
and:
R′ is Ac and R is H,
R′ is Ac, R is OMe,
R′ is Ac and R is OCH 2 CH 2 OMe,
R′ is Ac and R is F,
R′ is iBu and R is H,
R′ is iBu, R is OMe,
R′ is iBu and R is OCH 2 CH 2 OMe, or
R′ is iBu and R is F;
wherein X is
and:
R is H,
R is OMe,
R is OCH 2 CH 2 OMe, or
R is F;
wherein X is
and:
R is H,
R is OMe,
R is OCH 2 CH 2 OMe, or
R is F;
wherein X is
and:
R is H,
R is OMe,
R is OCH 2 CH 2 OMe, or
R is F;
wherein X is
and:
R is H,
R is OMe,
R is OCH 2 CH 2 OMe, or
R is F;
wherein X is
and:
R is H,
R is OMe,
R is OCH 2 CH 2 OMe, or
R is F;
wherein X is
and:
R is H,
R is OMe,
R is OCH 2 CH 2 OMe, or
R is F;
wherein X is
and:
R is H,
R is OMe,
R is OCH 2 CH 2 OMe, or
R is F;
wherein X is
and:
R is H,
R is OMe,
R is OCH 2 CH 2 OMe, or
R is F;
wherein X is
and:
R is H,
R is OMe,
R is OCH 2 CH 2 OMe, or
R is F;
wherein X is
and:
R is H,
R is OMe,
R is OCH 2 CH 2 OMe, or
R is F;
wherein X is
and:
R is H,
R is OMe,
R is OCH 2 CH 2 OMe, or
R is F; and
wherein X is
and:
R is H,
R is OMe,
R is OCH 2 CH 2 OMe, or
R is F.
29 . The composition of claim 28 , wherein the phosphoramidite is selected from:
30 . The composition of claim 28 , wherein the phosphoramidite is selected from:
wherein X is
and:
R′ is H and R is H,
R′ is H, R is OMe,
R′ is H and R is OCH 2 CH 2 OMe,
R′ is H and R is F,
R′ is Me and R is H,
R′ is Me, R is OMe,
R′ is Me and R is OCH 2 CH 2 OMe, or
R′ is Me and R is F;
wherein X is
and:
R′ is H and R is H,
R′ is H, R is OMe,
R′ is H and R is OCH 2 CH 2 OMe,
R′ is H and R is F,
R′ is Me and R is H,
R′ is Me, R is OMe,
R′ is Me and R is OCH 2 CH 2 OMe, or
R′ is Me and R is F;
wherein X is
and:
R′ is Ac and R is H,
R′ is Ac, R is OMe,
R′ is Ac and R is OCH 2 CH 2 OMe,
R′ is Ac and R is F,
R′ is iBu and R is H,
R′ is iBu, R is OMe,
R′ is iBu and R is OCH 2 CH 2 OMe, or
R′ is iBu and R is F;
wherein X is
and:
R′ is Ac and R is H,
R′ is Ac, R is OMe,
R′ is Ac and R is OCH 2 CH 2 OMe,
R′ is Ac and R is F,
R′ is iBu and R is H,
R′ is iBu, R is OMe,
R′ is iBu and R is OCH 2 CH 2 OMe, or
R′ is iBu and R is F;
wherein X is Ph
and:
R is H,
R is OMe,
R is OCH 2 CH 2 OMe, or
R is F; and
wherein X is
and:
R is H,
R is OMe,
R is OCH 2 CH 2 OMe, or
R is F.
31 . The composition of claim 28 , wherein the phosphoramidite is selected from:
wherein X is
and:
R is H,
R is OMe,
R is OCH 2 CH 2 OMe, or
R is F;
wherein X is
and:
R is H,
R is OMe,
R is OCH 2 CH 2 OMe, or
R is F;
wherein X is
and:
R is H,
R is OMe,
R is OCH 2 CH 2 OMe, or
R is F;
wherein X is
and:
R is H,
R is OMe,
R is OCH 2 CH 2 OMe, or
R is F;
wherein X is
and:
R is H,
R is OMe,
R is OCH 2 CH 2 OMe, or
R is F; and
wherein X is
and:
R is H,
R is OMe,
R is OCH 2 CH 2 OMe, or
R is F.
32 . The composition of claim 16 , wherein
wherein one R s is hydrogen, and the other R s is -L-R′, wherein R′ is —SO 2 R and L is a bivalent, optionally substituted C 1-30 aliphatic group.Join the waitlist — get patent alerts
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