Processes for preparing oligonucleotides
AssigneesChangzhou Syntheall Pharmaceuticals Co., Ltd., Shanghai Sta Pharmaceutical R&D Co., Ltd.
InventorsChenchen Hu, Qiang Zhao, Qing Li, Jimin Yang
Life of this patent
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Abstract
Disclosed are processes for preparing oligonucleotides. The process comprises: (a) converting a compound of Formula X-1 into a compound of Formula X-2: where R10 is a residue of an oligonucleotide (e.g., a phosphorodiamidate morpholino oligomer); R11 is an amine protecting group; wherein the compound of Formula X-1 is not bound to a solid support; and; (b) optionally removing protecting groups in the compound of Formula X-2 to obtain the olignucleotide. The synthetic processes described herein are advantageous in many aspects, including but not limited to improved yields and purities of target phosphorodiamidate morpholino oligomers with reduced 4-nitrostyrene adduct impurities. (X-1), (X-2)
Claims18
A process for preparing an oligonucleotide comprising:
- (a) converting a compound of Formula X-1 into a compound of Formula X-2:
- wherein:
- R10 is a residue of a phosphorodiamidate morpholino oligomer;
- R11 is an amine protecting group;
- wherein the compound of Formula X-1 is not bound to a solid support;
- and
- (b) optionally removing protecting groups in the compound of Formula X-2 to obtain the oligonucleotide,
- wherein the converting comprises adding the compound of Formula X-1 in a solution, into a mixture comprising an alkaline reagent, and a scavenger capable of reacting with the compound of Formula X-3:
- wherein the scavenger has a —SH or a 1,3-dicarbonyl moiety.
A process for preparing an oligonucleotide comprising:
- (a) converting a compound of Formula X-5 into a compound of Formula X-6:
- wherein:
- m1 and m2 are independently an integer of 0-50;
- R11 is an amine protecting group;
- Base at each occurrence is independently a base selected from G (guanine), C (cytosine), A (adenine), U (uracil), and T (thymine), modified analogs thereof, and protected derivatives thereof, provided that when the Base in Formula X-5 is a protected base, the corresponding Base in Formula X-6 can be the same protected base or a corresponding partially or fully deprotected base;
- wherein:
- T1 is a suitable 5′ terminal group;
- and
- T2 is a suitable 3′ terminal group;
- and
- (b) optionally partially or fully removing protecting groups in the compound of Formula X-6 to obtain the oligonucleotide.
Dependencies are inferred from the claim text.