US2020362339A1PendingUtilityA1
Processes for preparing phosphorodiamidate morpholino oligomers via fast-flow synthesis
Est. expirySep 25, 2037(~11.2 yrs left)· nominal 20-yr term from priority
C08G 79/02C12N 2310/3233C07F 9/65583C07F 9/65616C12N 2310/11C12N 2330/30C12N 2310/314C12N 15/113
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Claims
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.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . 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 R 2 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
R 1 is a support-medium; and
R 3 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
R 1 is a support-medium;
(b) contacting the compound of Formula (II) with a compound of Formula (A2):
wherein R 5 is
R 3 is selected from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl; and
R 4 is selected from the group consisting of:
to form a compound of Formula (A3):
wherein
B is
R 1 is a support-medium;
R 5 is
R 3 is selected from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl; and
R 4 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
R 1 is a support-medium;
R 6 is
and
R 4 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
R 3 is selected from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl; and
R 4 is selected from the group consisting of:
to form a compound of Formula (A5):
wherein R 7 is of Formula (A5a) or Formula (A5b):
B is
R 1 is a support-medium;
R 3 is selected from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl; and
R 4 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 R 7 is of the Formula (A5a) or Y is n−2 if R 7 is of the Formula (A5b);
R 3 is selected from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl; and
R 4 is, independently for each compound of Formula (A8), selected from the group consisting of:
to form a compound of Formula (A9):
(A9);
wherein R 8 is
B is
n is an integer from 9 to 39;
R 1 is a support-medium;
R 3 is selected from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl; and
R 4 is, independently for each occurrence, 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 R 9 is
B is
n is an integer from 9 to 39;
R 1 is a support-medium; and
R 4 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
R 9 is
C is
or H;
n is an integer from 9 to 39; and
R 4 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).
2 . The process of claim 1 , wherein one of steps (d) or (e2) further comprises contacting the compound formed by the immediately prior step with a capping agent.
3 . The process of claim 1 , wherein steps (a), (c), (e1), and (f) further comprise contacting the deblocked compound of each step with a neutralization agent.
4 . The process of claim 1 , wherein the compounds of Formula (A4) and Formula (A8) are each, independently, in a solution comprising N-ethylmorpholine and dimethylimidazolidinone.
5 . The process of claim 1 , wherein the cleavage agent comprises dithiothreitol and 1,8-diazabicyclo[5.4.0]undec-7-ene.
6 . The process of claim 1 , wherein for steps (a)-(g), B is
and for step (h), C is
7 . The process according to claim 1 , wherein any of steps (a), (b), (c), (d), (e1), (e2), (f), (g), or (h) are carried out in a batchwise synthesis or in a continuous synthesis.
8 . A continuous process for preparing an oligomeric compound of Formula (A11):
wherein R 9 is
C is
n is an integer from 9 to 39; and
R 4 is, independently for each occurrence, selected from the group consisting of:
wherein the process comprises the sequential steps of:
(a) contacting a deblocking agent with a compound of Formula (A3):
wherein B is
R 1 is a support-medium;
R 5 is
and
R 3 is selected from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl;
in a reactor vessel to form a compound of Formula (IV):
wherein B is
R 1 is a support-medium;
R 6 is
(b) washing the compound of Formula (IV) with a washing solvent and a neutralizing agent, wherein the washing comprises passing a washing solvent and a neutralizing agent through the reactor vessel;
(c) washing the compound of Formula (IV) with a washing solvent, wherein the washing comprises passing a washing solvent through the reactor vessel;
(d) washing the compound of Formula (IV) with a coupling solvent, wherein the washing comprises passing a coupling solvent through the reactor vessel;
(e) introducing to the reactor vessel a lewis acid and a compound of Formula (A4):
wherein
R 3 is selected from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl; and
R 4 is selected from the group consisting of:
such that the compound of formula (A4) contacts the compound of Formula (IV) to form a compound of Formula (A5):
wherein R 7 is of the Formula (A5a) or Formula (A5b):
B is
R 1 is a support-medium;
R 3 is selected from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl; and
R 4 is selected from:
(f) washing the compound of Formula (A5) with a coupling solvent, wherein the washing comprises passing a coupling solvent through the reactor vessel;
(g) performing Y iterations of the sequential steps of:
(g1) washing the product formed by the immediately prior step with a washing solvent, wherein the washing comprises passing a washing solvent through the reactor vessel;
(g2) introducing a deblocking agent into the reactor vessel such that it contacts the product formed by the immediately prior step;
(g3) washing the product formed by the immediately prior step with a washing solvent and a neutralizing agent, wherein the washing comprises passing a washing solvent and a neutralizing agent through the reactor vessel;
(g4) washing the product formed by the immediately prior step with a washing solvent, wherein the washing comprises passing a washing solvent through the reactor vessel;
(g5) washing the product formed by the immediately prior step with a coupling solvent, wherein the washing comprises passing a coupling solvent through the reactor vessel;
(g6) introducing to the reactor vessel containing the product formed by the immediately prior step a lewis acid and a compound of Formula (A8):
wherein
Y is n−1;
R 3 is selected from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl; and
R 4 is, independently for each compound of Formula (A8), selected from the group consisting of:
such that the compound of Formula (A8) contacts the compound formed by the immediately prior step to form a compound of Formula (A9):
wherein R 8 is
B is
n is an integer from 9 to 39;
R 1 is a support-medium;
R 3 is selected from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl; and
R 4 is, independently for each occurrence, selected from the group consisting of:
(h) washing the compound of Formula (A9) with a coupling solvent to remove the compound of Formula (A8), wherein the washing comprises passing a coupling solvent through the reactor vessel;
(i) washing the compound of Formula (A9) with a washing solvent to remove the coupling solvent, wherein the washing comprises passing a washing solvent through the reactor vessel;
(j) contacting a deblocking agent with a compound of Formula (A9) in a reactor vessel to form a compound of Formula (A10):
wherein R 9 is
B is
n is an integer from 9 to 39;
R 1 is a support-medium; and
R 4 is, independently for each occurrence, selected from the group consisting of:
and
(k) contacting a cleaving agent with a compound of Formula (10) in a reactor vessel to form a compound of Formula (A11).
9 . The process of claim 8 , wherein steps (a), (g2), and (j) further comprise contacting the deblocked compound of each respective step with a neutralization agent.
10 . The process of claim 8 , wherein the washing solvent is a halogenated solvent.
11 . The process of claim 8 , wherein the coupling solvent is 1,3-dimethyl-2-imidazolidinone or N-methyl-2-pyrrolidone.
12 . The process of claim 8 , wherein for steps (a)-(j), B is
and for step (k), C is
13 . The process of claim 8 , wherein any of steps (a), (b), (c), (d), (e), (f), (g1), (g2), (g3), (g4), (g5), (g6), (h), (i), (j), and (k) are optionally carried out in a batchwise process.
14 . The process of claim 8 , wherein the process is performed in a flow-through reactor, the flow-through reactor comprising at least:
(a) a feeding zone, wherein the feeding zone comprises one or more feed lines each equipped with a pump, and wherein the inlet zones of the feed lines are independently connected to vessels comprising a neutralizing agent, coupling solvent, a deblocking agent, washing solvent, and a compound of Formula (A8):
wherein
R 3 is selected from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl; and
R 4 is, independently for each compound of Formula (A8), selected from the group consisting of:
wherein the compound of Formula (A8) is dissolved in a coupling solvent;
(b) a reaction zone that is connected to the outlet zone of the one or more feed lines and which contains a PMO synthesis resin;
(c) an outlet zone, whereby waste stream or product can be independently collected;
(d) a pressure control device; and
(e) a means of independently controlling the temperature of the feeding zone and the reaction zone.
15 . The process of claim 14 , wherein the flow-through reactor is used for the preparation of Eteplirsen.
16 . The process of claim 1 , wherein the deblocking agent is selected from the group consisting of chloroacetic acid, dichloroacetic acid, trichloroacetic acid, fluoroacetic acid, difluoroacetic acid, and trifluoroacetic acid.
17 . The process of claim 1 , wherein the deblocking agent used in each step is a solution comprising a halogenated acid.
18 . The process of claim 1 , wherein the Lewis acid is selected from a group consisting of LiCl, LiBr, LiI, and LiOTf.
19 . The process of claim 1 , wherein the neutralization agent is in a solution comprising a halogenated solvent and isopropyl alcohol.
20 . The process of claim 1 , wherein the neutralization agent is a monoalkyl, dialkyl, or trialkyl amine.Join the waitlist — get patent alerts
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