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US 2019/0375774 A1Published application
Compositions and methods for phosphoramidite and oligonucleotide synthesis
AssigneeWave Life Sciences Ltd.
InventorsDavid Charles Donnell Butler, Pachamuthu Kandasamy, Subramanian Marappan, Ik-Hyeon Paik, Jayakanthan Kumarasamy, Gopal Reddy Bommineni
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Abstract
The present disclosure, among other things, provides technologies for oligonucleotide synthesis. In some embodiments, the present disclosure provides phosphoramidites and methods for synthesis thereof. In some embodiments, provided methods provides higher yields and/or purities. In some embodiments, provided methods remove byproducts without contact with an aqueous solution.
Claims33
A method for preparing a phosphoramidite, comprising steps of:
- a) providing a preparation comprising a phosphoramidite product and one or more reaction byproducts of the product's synthesis;
- and
- b) performing a filtration step on the preparation to provide a filtrate, wherein the filtrate contains a reduced level of the one or more reaction byproducts relative to the product as compared to that level present in the preparation prior to the filtration step.
In a method of preparing a phosphoramidite that includes a step of separating a phosphoramidite product from one or more reaction byproducts of the product's synthesis, the improvement comprising:
- subjecting a preparation comprising the phosphoramidite product and the one or more reaction byproducts to filtration without adding a material amount of water to the preparation after the phosphoramidite product has been formed.
In a method of preparing a phosphoramidite that includes a step of separating a phosphoramidite product from one or more reaction byproducts of the product's synthesis, the improvement comprising:
- subjecting a preparation comprising the phosphoramidite product and the one or more reaction byproducts to filtration without adding a material amount of any aqueous or halogenated solvent to the preparation after the phosphoramidite product has been formed.
In a method of preparing a phosphoramidite that includes a step of separating a phosphoramidite product from one or more reaction byproducts of the product's synthesis, the improvement comprising:
- subjecting a preparation comprising the phosphoramidite product and the one or more reaction byproducts to filtration without adding a material amount of any aqueous solvent, or performing any extraction from an aqueous solvent, after the phosphoramidite product has been formed.
A compound having the structure of formula I:
- or a salt thereof, wherein:
- BA is protected
- wherein O6 is not protected;
- SU is -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 C1-30 aliphatic and C1-30 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 C1-6 alkylene, C1-6 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)2N(R′)—, —N(R′)S(O)2—, —SC(O)—, —C(O)S—, —OC(O)—, or —C(O)O—;
- R5s is R′ or —OR′;
- R2s is —F, —CN, —N3, —NO, —NO2, —R′—OR′, —SR′, —N(R′)2, —O-L-OR′, —O-L-SR′, or —O-L-N(R′)2, or R2s 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;
- each of R1, R2, and R3 is independently R′, wherein two or three of R1, R2, and R3 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 Rs is independently R′ or -L-R′;
- t is 0-5;
- each R′ is independently —R, —C(O)R, —CO2R, or —SO2R, 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 C1-30 aliphatic, C1-30 heteroaliphatic having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, C6-30 aryl, 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.
14 more elements
A compound having the structure of formula I:
- or a salt thereof, wherein:
- BA is substituted
- wherein O6 is not substituted;
- SU is -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 C1-30 aliphatic and C1-30 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 C1-6 alkylene, C1-6 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)2N(R′)—, —N(R′)S(O)2—, —SC(O)—, —C(O)S—, —OC(O)—, or —C(O)O—;
- R5s is R′ or —OR′;
- R2s is —F, —CN, —N3, —NO, —NO2, —R′—OR′, —SR′, —N(R′)2, —O-L-OR′, —O-L-SR′, or —O-L-N(R′)2, or R2s 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;
- each of R1, R2, and R3 is independently R′, wherein two or three of R1, R2, and R3 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 Rs is independently R′ or -L-R′;
- t is 0-5;
- each R′ is independently —R, —C(O)R, —CO2R, or —SO2R, 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 C1-30 aliphatic, C1-30 heteroaliphatic having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, C6-30 aryl, 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.
14 more elements
A compound having the structure of formula I:
- or a salt thereof, wherein:
- BA is
- SU is -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 C1-30 aliphatic and C1-30 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 C1-6 alkylene, C1-6 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)2N(R′)—, —N(R′)S(O)2—, —SC(O)—, —C(O)S—, —OC(O)—, or —C(O)O—;
- R5s is R′ or —OR′;
- R2s is —F, —CN, —N3, —NO, —NO2, —R′—OR′, —SR′, —N(R′)2, —O-L-OR′, —O-L-SR′, or —O-L-N(R′)2, or R2s 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;
- each of R1, R2, and R3 is independently R′, wherein two or three of R1, R2, and R3 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 Rs is independently R′ or -L-R′;
- t is 0-5;
- each R′ is independently —R, —C(O)R, —CO2R, or —SO2R, 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 C1-30 aliphatic, C1-30 heteroaliphatic having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, C6-30 aryl, 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.
13 more elements
A compound or a salt thereof, wherein the compound is an oligonucleotide comprising one or more base moieties BA, wherein BA is protected
- wherein O6 is not protected.
A compound or a salt thereof, wherein the compound is an oligonucleotide comprising one or more base moieties BA, wherein BA is substituted
- wherein O6 is not substituted.
A compound selected from:
A compound or method of any one of embodiments 1-265.
Dependencies are inferred from the claim text.