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US 12,077,558 B2Granted
Phosphorus (V)-based reagents, processes for the preparation thereof, and their use in making stereo-defined organophosphorus (V) compounds
AssigneesBristol-Myers Squibb Company, The Scripps Research Institute
InventorsMichael Anthony Schmidt, Bin Zheng, Kyle Knouse, Justine deGruyter, Martin D. Eastgate, Phil Baran, William R. Ewing, Richard E. Olson, Ivar M. McDonald
Life of this patent
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Abstract
The present invention relates to novel phosphorous (V) (P(V)) reagents, methods for preparing thereof, and methods for preparing organophosphorous (V) compounds by using the novel reagents.
Claims20
A stereochemically pure compound of formula IV:
- wherein
- (a) R1, R2, R3, R4, R5, and R6 are independently hydrogen, CD3, CF3, linear or branched C1-C20 alkyl, optionally substituted with one or more, the same or different, Ra groups;
- linear or branched C2-C12 alkenyl;
- optionally substituted with one or more, the same or different, Ra groups;
- linear or branched C2-C12 alkynyl, optionally substituted with one or more, the same or different, Ra groups;
- aryl, optionally substituted with one or more, the same or different, Ra groups;
- heteroaryl, optionally substituted with one or more, the same or different, Ra groups;
- heterocyclyl, optionally substituted with one or more, the same or different, Ra groups;
- or C3-C8 cycloalkyl, optionally substituted with one or more, the same or different, Ra groups;
- or
- (b) any two of R1, R2, R3, R4, R5, and R6 together with the carbons to which they are attached form a C4-C8 cycloalkyl group, optionally substituted with one or more, the same or different, Ra groups, while the remaining R1, R2, R3, R4, R5, and R6 are as defined in (a);
- Ra is hydrogen, deuterium, CD3, C1-C6 alkyl, OH, halogen, CN, CF3, O—C1-C6 alkyl, O-aryl, O-heteroaryl, O—C3-C8 cycloalkyl, O-heterocyclyl, —NRbRb, —COORb or —CONRbRb;
- Rb is independently at each occurrence, the same or different, hydrogen, linear or branched C1-C12 alkyl, aryl, heteroaryl, heterocyclyl or C3-C8 cycloalkyl;
- X1 is O, X2 is S;
- or X1 is S, X2 is O;
- Y is O, S or NRc;
- Rc is hydrogen;
- m is 0, 1 or 2, and
- Nu is a nucleoside, wherein the phosphorus atom is covalently bonded to a 5′- or 3′-oxygen atom on the nucleoside sugar;
- with the proviso that the compound of formula IV does not include the following compounds:
17 more elements
A method of making an oligonucleotide, comprising:
- a) reacting the compound of formula I with a first nucleoside having a hydroxy group on the 5′ or 3′ carbon of the nucleoside sugar, in the presence of a base to form a loaded nucleoside, wherein formula I is
- wherein
- (a) R1, R2, R3, R4, R5, and R6 are independently hydrogen, CD3 or CF3, linear or branched C1-C20 alkyl, optionally substituted with one or more, the same or different, Ra groups;
- linear or branched C2-C12 alkenyl;
- optionally substituted with one or more, the same or different, Ra groups;
- linear or branched C2-C12 alkynyl, optionally substituted with one or more, the same or different, Ra groups;
- aryl, optionally substituted with one or more, the same or different, Ra groups;
- heteroaryl, optionally substituted with one or more, the same or different, Ra groups;
- heterocyclyl, optionally substituted with one or more, the same or different, Ra groups;
- or C3-C8 cycloalkyl, optionally substituted with one or more, the same or different, Ra groups;
- or
- (b) any two of R1, R2, R3, R4, R5, and R6 together with the carbons to which they are attached form a C4-C8 cycloalkyl group, optionally substituted with one or more, the same or different, Ra groups, while the remaining R1, R2, R3, R4, R5, and R6 are as defined in (a);
- Ra is hydrogen;
- deuterium, CD3, C1-C6 alkyl, OH, halogen, CN, CF3, O—C1-C6 alkyl, O-aryl, O-heteroaryl, O—C3-C8 cycloalkyl, O-heterocyclyl, —NRbRb, —COORb or —CONRbRb;
- Rb is independently at each occurrence, the same or different, hydrogen, linear or branched C1-C12 alkyl, aryl, heteroaryl, heterocyclyl or C3-C8 cycloalkyl;
- X1 is O, X2 is S;
- or X1 is S, X2 is O;
- Y is O, S or NRc;
- m is 0, 1 or 2,
- and
- LG is a leaving group;
- selected from the group consisting of
- wherein the compound of any one of formulae I is at least 90% stereochemically pure;
- b) reacting the loaded nucleoside formed in step (a) with a second nucleoside, thereby coupling the two nucleosides to form a dinucleotide;
- c) adding a compound of formula I as defined above to the dinucleotide to form a loaded dinucleotide;
- d) adding another nucleoside to the loaded dinucleotide, thereby adding an additional nucleoside to said dinucleotide;
- and
- e) repeating steps (c) and (d) one or more times to form an oligonucleotide having a desired number of nucleotides.
25 more elements
Dependencies are inferred from the claim text.