Back to results
US 12,590,306 B2Granted
Processes for preparing phosphorodiamidate morpholino oligomers via fast-flow synthesis
AssigneesSarepta Therapeutics, Inc., Massachusetts Institute of Technology
InventorsKyle A. Totaro, Mark D. Simon, Ming Zhou, Hong Zong, Gunnar J. Hanson, Bradley L. Pentelute
Life of this patent
Estimating the term…
Abstract
Provided herein are processes for preparing an oligomer (e.g., a morpholino oligomer). The synthetic processes described herein may be advantageous to scaling up oligomersynthesis while maintaining overall yield and purity of a synthesized oligomer.
Claims13
A process for preparing an oligomeric compound of Formula (I):
- wherein
- n is an integer from 9 to 39;
- T is OH or
- and
- each R2 is, independently for each occurrence, selected from the group consisting of:
- wherein the process comprises the sequential steps of:
- (a) contacting a compound of Formula (A1):
- wherein
- B is
- R1 is a support-medium;
- and
- R3 is selected from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl;
- with a deblocking agent to form the compound of Formula (II):
- wherein B is
- and
- R1 is a support-medium;
- (b) contacting the compound of Formula (II) with a compound of Formula (A2):
- wherein R5 is
- R3 is selected from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl;
- and
- R4 is selected from the group consisting of:
- to form a compound of Formula (A3):
- wherein
- B is
- R1 is a support-medium;
- R5 is
- R3 is selected from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl;
- and
- R4 is selected from the group consisting of:
- (c) contacting the compound of Formula (A3) with a deblocking agent to form a compound of Formula (IV):
- wherein B is
- R1 is a support-medium;
- R6 is
- and
- R4 is selected from the group consisting of:
- (d) contacting the compound of Formula (IV) with a compound of Formula (A4):
- in the presence of a Lewis acid catalyst;
- wherein
- R3 is selected from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl;
- and
- R4 is selected from the group consisting of:
- to form a compound of Formula (A5):
- wherein R7 is of Formula (A5a) or Formula (A5b):
- B is
- R1 is a support-medium;
- R3 is selected from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl;
- and
- R4 is selected from:
- (e) performing Y iterations of the sequential steps of:
- (e1) contacting the product formed by the immediately prior step with a deblocking agent;
- and
- (e2) contacting the compound formed by the immediately prior step with a compound of Formula (A8):
- in the presence of a Lewis acid catalyst;
- wherein
- Y is n−1 if R7 is of the Formula (A5a) or Y is n−2 if R7 is of the Formula (A5b);
- R3 is selected from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl;
- and
- R4 is, independently for each compound of Formula (A8), selected from the group consisting of:
- to form a compound of Formula (A9):
- wherein R8 is
- B is
- n is an integer from 9 to 39;
- R1 is a support-medium;
- R3 is selected from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl;
- and
- R4 is, independently for each occurrence, selected from the group consisting of:
- (f) contacting the compound of Formula (A9) with a deblocking agent to form a compound of Formula (A10):
- wherein R9 is
- B is
- n is an integer from 9 to 39;
- R1 is a support-medium;
- and
- R4 is, independently for each occurrence, selected from the group consisting of:
- (g) contacting the compound of Formula (A10) with a cleaving agent to form a compound of Formula (A11):
- wherein
- R9 is
- C is
- or H;
- n is an integer from 9 to 39;
- and
- R4 is, independently for each occurrence, selected from the group consisting of:
- and
- (h) contacting the compound of Formula (A11) with a deprotecting agent to form the oligomeric compound of Formula (I),
- wherein any of steps (a), (b), (c), (d), (e1), (e2), (f), (g), or (h) are carried out in a continuous synthesis.
81 more elements
Dependencies are inferred from the claim text.