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US 10,947,533 B2Granted
Processes for preparing phosphorodiamidate morpholino oligomers
AssigneeSarepta Therapeutics, Inc.
InventorsBaozhong Cai, Mitchell Martini, Katie Thomas, Ross Shimabuku
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 oligomer synthesis while maintaining overall yield and purity of a synthesized oligomer.
Claims21
A process for preparing an oligomeric compound of Formula (C):
- or a pharmaceutically acceptable salt thereof,
- wherein the process comprises the sequential steps of:
- (a) contacting a compound of Formula (A1):
- wherein 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 R1 is a support-medium;
- (b) contacting the compound of Formula (II) with a compound of Formula (A2):
- wherein R3 is selected from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl;
- to form a compound of Formula (A3):
- wherein R1 is a support-medium, and R3 is selected from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl;
- (c) contacting the compound of Formula (A3) with a deblocking agent to form a compound of Formula (IV):
- wherein R1 is a support-medium;
- (d) contacting the compound of Formula (IV) with a compound of Formula (A4):
- wherein R3 is selected from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl, and R4 is:
- to form a compound of Formula (A5):
- wherein R1 is a support-medium, R3 is selected from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl, and
- R4 is:
- (e) performing 21 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):
- wherein R3 is selected from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl, and R4 is, as per the oligomeric compound of Formula (C), selected from the group consisting of:
- to form a compound of Formula (A9):
- wherein n is 22, R1 is a support-medium, R3 is selected from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl, and R4 is, per the oligomeric compound of Formula (C), selected from the group consisting of:
- and
- (f) contacting the compound of Formula (A9) with a deblocking agent to form a compound of Formula (A10):
- wherein n is 22, R1 is a support-medium, and R4 is, as per the oligomeric compound of Formula (C), 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 n is 22, and R4 is, as per the oligomeric compound of Formula (C), 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 (C).
28 more elements
A compound of Formula (IX):
- or a pharmaceutically acceptable salt thereof, wherein:
- R1 is a support-medium, and
- R2 is at each position from 1 to 22 and 5′ to 3′:
- Position No. 5′ to 3′
- R2
- 1
- PC
- 2
- PA
- 3
- PA
- 4
- T
- 5
- DPG
- 6
- PC
- 7
- PC
- 8
- PA
- 9
- T
- 10
- PC
- 11
- PC
- 12
- T
- 13
- DPG
- 14
- DPG
- 15
- PA
- 16
- DPG
- 17
- T
- 18
- T
- 19
- PC
- 20
- PC
- 21
- T
- 22
- DPG
- PC is
- DPG is
- T is
- and PA is
50 more elements
A compound of Formula (X):
- or a pharmaceutically acceptable salt thereof, wherein
- R1 is a support-medium, and
- R2 is at each position from 1 to 22 and 5′ to 3′:
- Position No. 5′ to 3′
- R2
- 1
- PC
- 2
- PA
- 3
- PA
- 4
- T
- 5
- DPG
- 6
- PC
- 7
- PC
- 8
- PA
- 9
- T
- 10
- PC
- 11
- PC
- 12
- T
- 13
- DPG
- 14
- DPG
- 15
- PA
- 16
- DPG
- 17
- T
- 18
- T
- 19
- PC
- 20
- PC
- 21
- T
- 22
- DPG
- wherein PC is
- DPG is
- T is
- and PA is
50 more elements
A compound of Formula (XI):
- or a pharmaceutically acceptable salt thereof, wherein:
- R2 is at each position from 1 to 22 and 5′ to 3′:
- Position No. 5′ to 3′
- R2
- 1
- PC
- 2
- PA
- 3
- PA
- 4
- T
- 5
- DPG
- 6
- PC
- 7
- PC
- 8
- PA
- 9
- T
- 10
- PC
- 11
- PC
- 12
- T
- 13
- DPG
- 14
- DPG
- 15
- PA
- 16
- DPG
- 17
- T
- 18
- T
- 19
- PC
- 20
- PC
- 21
- T
- 22
- DPG
- wherein PC is
- DPG is
- T is
- and PA is
49 more elements
Dependencies are inferred from the claim text.