Tricyclo-dna nucleoside precursors and processes for preparing the same
AssigneeSynthena AG
InventorsBranislav Dugovic, Reto Bertolini
Life of this patent
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Abstract
The present invention relates to a process for preparing tc-DNA nucleoside precursors, the resulting tc-DNA nucleosides, and oligonucleotides comprising such tc-DNA nucleosides. In an embodiment of the invention, the process includes use of a carbene precursor.
Claims11
A method of preparing a tc-DNA nucleoside precursor, the method comprising the steps of:
- a. preparing a carbene precursor at a carbene preparation temperature;
- b. adding a compound of Formula X, Formula XI, or Formula XII:
- to the carbene precursor at a cyclopropanation temperature;
- and
- c. providing the tc-DNA nucleoside precursor of one of Formulas I-IX,
- wherein Y is alkoxy;
- T3 and T4 are each OR5, where each R5 is H or a hydroxyl protecting group;
- q6, q7, and q8 are each independently selected from the group consisting of hydrogen, halogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, substituted C1-6alkyl, substituted C2-6alkenyl, substituted C2-6alkynyl, and —(CH2)n—C(O)—R6, wherein n is 0 to 6 and wherein R6 is selected from the group consisting of OH, NH2, O—C1-32alkyl and NH—C1-32 alkyl;
- and
- z3 and z4 are each independently selected from the group consisting of hydrogen, C1-6alkyl, C1-6alkoxyl, O—C2-6alkenyl, O—C2-6alkynyl, substituted C1-6alkyl, substituted C1-6alkoxy, substituted O—C2-6alkenyl, and substituted O—C2-6alkynyl halogen.
A method of preparing a tc-DNA nucleoside precursor, the method comprising the steps of:
- a. preparing a carbene precursor at a carbene preparation temperature;
- b. preparing a solution of a compound of Formula X, Formula XI, or Formula XII:
- c. adding the carbene precursor to the solution of the compound of Formula X, Formula XI, or Formula XII, at a cyclopropanation temperature;
- and
- d. providing the tc-DNA nucleoside precursor of one of Formulas I-IX,
- wherein Y is alkoxy;
- T3 and T4 are each OR5, where R5 is H or a hydroxyl protecting group;
- q6, q7, and q8 are each independently selected from the group consisting of hydrogen, halogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, substituted C1-6alkyl, substituted C2-6alkenyl, substituted C2-6alkynyl, and —(CH2)n—C(O)—R6, wherein n is 0 to 6 and wherein R6 is selected from the group consisting of OH, NH2, O—C1-32alkyl and NH—C1-32alkyl;
- and
- z3 and z4 are each independently selected from the group consisting of hydrogen, C1-6alkyl, C1-6alkoxyl, O—C2-6alkenyl, O—C2-6alkynyl, substituted C1-6alkyl, substituted C1-6alkoxy, substituted O—C2-6alkenyl, and substituted O—C2-6alkynyl halogen.
The method of any of the preceding claims, comprising the step of adding a Lewis acid catalyst to the mixture of the compound of Formula X, Formula XI, or Formula XII and the carbene precursor
The method of any of the preceding claims, wherein the step of preparing the carbene precursor comprises combining a Lewis acid catalyst and R7I2 in a solvent, wherein R7 is selected from the group consisting of CH2, CH—C1-6alkyl, CH—C2-6alkenyl, CH—C2-6alkynyl, substituted CH—C1-6alkyl, substituted CH—C2-6alkenyl, substituted CH—C2-6alkynyl, and CH—(CH2)n—C(O)—R8, wherein n is 0 to 6 and wherein R8 is selected from the group consisting of OH, NH2, O—C1-32alkyl and NH—C1-32alkyl.
The method of any of the preceding claims, wherein the carbene precursor is Q3CCO2ZnR7I, Q3CCH2OZnR7I, (n-BuO)2P(O)OZnR7I, (alkyl-O)2P(O)OZnR7I, (aryl-O)2P(O)OZnR7I, or 2,4,6—Cl3C6H2OZnR7I, wherein each Q is independently selected from the group consisting of H, Cl, Br, and F, and R7 is selected from the group consisting of CH2, CH—C1-6alkyl, CH—C2-6alkenyl, CH—C2-6alkynyl, substituted CH—C1-6alkyl, substituted CH—C2-6alkenyl, substituted CH—C2-6alkynyl, and CH—(CH2)n—C(O)—R8, wherein n is 0 to 6 and wherein R1 is selected from the group consisting of OH, NH2, O—C1-32alkyl and NH—C1-32alkyl.
The method of any of the preceding claims, wherein the carbene precursor is CCl3CO2ZnCH2I, CF3CH2OZnCH2I, (n-BuO)2P(O)OZnCH2I, or 2,4,6—Cl3C6H2OZnCH2I.
Dependencies are inferred from the claim text.