Synthesis of locked nucleic acid derivatives
AssigneeSantaris Pharma A/S
InventorsMads Detlef Sørensen, Jesper Wengel, Troels Koch, Signe M. Christensen, Christoph Rosenbohm, Daniel Sejer Pedersen
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Abstract
The invention relates to a novel strategy for the synthesis of Locked Nucleic Acid derivatives, such as α-L-oxy-LNA, amino-LNA, α-L-amino-LNA, thio-LNA, α-L-thio-LNA, seleno-LNA and methylene LNA, which provides scalable high yielding reactions utilizing intermediates that also can produce other LNA analogues such as oxy-LNA. Also, the compounds of the formula X are important intermediates that may be reacted with varieties of nucleophiles leading to a wide variety of LNA analogues.
Claims8
A method for the synthesis of a compound of formula IV
- wherein
- X is O;
- Z is S;
- B is a nucleobase;
- R3 is selected from —RH, —N3, —NRHRH*, —NRHC(O)RH*, —C(O)NRHRH*, —ORH, —OC(O)RH, —C(O)ORH, —SRH, —SC(O)RH, and tri(C1-6-alkyl/aryl)silyloxy;
- each RH and RH* independently being selected from hydrogen, optionally substituted C1-6-alkyl, optionally substituted aryl, and optionally substituted aryl-C1-6-alkyl;
- A4 and A5 independently are selected from C1-6-alkylene;
- and
- R5 is selected from iodo, bromo, chloro, C1-6-alkylsulfonyloxy, cyclohexanesulfonyloxy and cyclopentanesulfonyloxy, each optionally substituted with one or more halogen, and arylsulfonyloxy optionally substituted with one or more substituents selected from nitro, halogen, C1-6-alkyl, and C1-6-alkyl substituted with one or more halogen;
- said method comprising the following steps:
- treating an intermediate of the formula I:
- wherein
- X, B, R3, A4, and A5 are as defined above;
- R2 is selected from iodo, C1-6-alkylsulfonyloxy optionally substituted with one or more halogen and arylsulfonyloxy optionally substituted with one or more substituents selected from nitro, halogen, C1-6-alkyl, and C1-6-alkyl substituted with one or more halogen;
- R3 and R2 may together form an epoxide and R4 and R5 independently are as defined for R5 above, or R4 and R5 together constitutes a tetra(C1-6-alkyl)disiloxanylidene group;
- with a nucleophile selected from Na2S and potassium thioacetate, so as to substitute R2, and
- effecting ring-closure between the C2′ and C4′ positions under the influence of lithium hydroxide in a polar aprotic solvent so as to yield the compound formula IV.
Dependencies are inferred from the claim text.