US 2019/0292208 A1Published application

Processes for preparing phosphorodiamidate morpholino oligomers

AssigneeSarepta Therapeutics, Inc.

InventorsBao CAI, Mitchell MARTINI, Katie THOMAS, Ross SHIMABUKU

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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.

Claims23

Dependent claims

A process for preparing an oligomeric compound of Formula (A):

wherein n is an integer from 10 to 40, 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 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 selected from the group consisting of:
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 selected from:
(e) performing n−1 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, independently for each compound of Formula (A8), selected from the group consisting of:
to form a compound of Formula (A9):
wherein n is an integer from 10 to 40, 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 n is an integer from 10 to 40, 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 n is an integer from 10 to 40, and R4 is, independently for each occurrence, selected from the group consisting of:
and
(g) contacting the compound of Formula (A11) with a deprotecting agent to form the oligomeric compound of Formula (A).

27 more elements

A process for preparing an oligomeric compound of Formula (G):

wherein the process comprises the sequential steps of:
(a) contacting a compound of Formula (I):
wherein R1 is a support-medium,
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 compound (B):
to form a compound of Formula (III):
wherein R1 is a support-medium;
(c) contacting the compound of Formula (III) 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 (DPG):
to form a compound of Formula (V):
wherein R1 is a support-medium;
(e) contacting the compound of Formula (V) with a deblocking agent to form a compound of Formula (VI):
wherein R1 is a support-medium;
(f) contacting the compound of Formula (VI) with compound of Formula (T):
to form a compound of Formula (VII):
wherein R1 is a support-medium;
(g) performing 23 iterations of the sequential steps of:
(g1) contacting the product formed by the immediately prior step with a deblocking agent;
and
(g2) contacting the compound formed by the immediately prior step with a compound of Formula (VIII):
wherein R2 is, independently for each compound of Formula (VIII), selected from the group consisting of:
wherein, for each iteration from 1 to 23, R2 is:
Iteration No.
R2
1
T
2
DPG
3
PC
4
PC
5
T
6
PC
7
PC
8
DPG
9
DPG
10
T
11
T
12
PC
13
T
14
DPG
15
PA
16
PA
17
DPG
18
DPG
19
T
20
DPG
21
T
22
T
23
PC
to form a compound of Formula (IX):
wherein R1 is a support-medium,
wherein R2 is, independently for each occurrence, selected from the group consisting of:
and
wherein R2 is at each position from 1 to 25 and 5′ to 3′:
Position No.
5′ to 3′
R2
1
DPG
2
T
3
T
4
DPG
5
PC
6
PC
7
T
8
PC
9
PC
10
DPG
11
DPG
12
T
13
T
14
PC
15
T
16
DPG
17
PA
18
PA
19
DPG
20
DPG
21
T
22
DPG
23
T
24
T
25
PC
(h) contacting the compound of Formula (IX) with a deblocking agent to form a compound of Formula (X):
wherein R1 is a support-medium,
wherein R2 is, independently for each occurrence, selected from the group consisting of:
and
wherein R2 is at each position from 1 to 25 and 5′ to 3′:
Position No.
5′ to 3′
R2
1
DPG
2
T
3
T
4
DPG
5
PC
6
PC
7
T
8
PC
9
PC
10
DPG
11
DPG
12
T
13
T
14
PC
15
T
16
DPG
17
PA
18
PA
19
DPG
20
DPG
21
T
22
DPG
23
T
24
T
25
PC
(i) contacting the compound of Formula (X) with a cleaving agent to form a compound of Formula (XI):
wherein R2 is, independently for each occurrence, selected from the group consisting of:
and
wherein R2 is at each position from 1 to 25 and 5′ to 3′:
Position No.
5′ to 3′
R2
1
DPG
2
T
3
T
4
DPG
5
PC
6
PC
7
T
8
PC
9
PC
10
DPG
11
DPG
12
T
13
T
14
PC
15
T
16
DPG
17
PA
18
PA
19
DPG
20
DPG
21
T
22
DPG
23
T
24
T
25
PC
and
(j) contacting the compound of Formula (XI) with a deprotecting agent to form the oligomeric compound of Formula (G).

244 more elements

Dependencies are inferred from the claim text.

Facts

Application: 16/302,529Filed 30 Jun 2017
Priority: 24 May 2016
Published: 26 Sep 2019
Term ends: Not estimatedThe source records don’t support an estimate.

Classification11 codes

C07F 9/6533
Having nitrogen and oxygen atoms as the only ring hetero atoms: six-membered rings
C07F 9/6512
Six-membered rings: having the nitrogen atoms in positions 1 and 3
C07F 9/65583
Containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common…: each of…
C07F 9/65616
Containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system,…:…

Family

Application62/341,049Us provisional application · filed 24 May 2016
Application62/340,953Us provisional application · filed 24 May 2016
Application62/357,134Us provisional application · filed 30 Jun 2016
Application62/357,166Us provisional application · filed 30 Jun 2016
Application62/508,256Us provisional application · filed 18 May 2017
US 11,472,824 B2Related patent
US 2019/0292208 A1This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

A process for preparing an oligomeric compound of Formula (A):

wherein n is an integer from 10 to 40, 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 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 selected from the group consisting of:
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 selected from:
(e) performing n−1 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, independently for each compound of Formula (A8), selected from the group consisting of:
to form a compound of Formula (A9):
wherein n is an integer from 10 to 40, 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 n is an integer from 10 to 40, 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 n is an integer from 10 to 40, and R4 is, independently for each occurrence, selected from the group consisting of:
and
(g) contacting the compound of Formula (A11) with a deprotecting agent to form the oligomeric compound of Formula (A).

27 more elements

Facts

Application

16/302,529Filed 30 Jun 2017

Priority

24 May 2016

Published

26 Sep 2019

Term ends

Not estimatedThe source records don’t support an estimate.

Classification11 codes

C07F 9/6533
Having nitrogen and oxygen atoms as the only ring hetero atoms: six-membered rings
C07F 9/6512
Six-membered rings: having the nitrogen atoms in positions 1 and 3
C07F 9/65583
Containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common…: each of…
C07F 9/65616
Containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system,…:…

Family

Application62/341,049Us provisional application · filed 24 May 2016

Application62/340,953Us provisional application · filed 24 May 2016

Application62/357,134Us provisional application · filed 30 Jun 2016

Application62/357,166Us provisional application · filed 30 Jun 2016

Application62/508,256Us provisional application · filed 18 May 2017

US 11,472,824 B2Related patent

US 2019/0292208 A1This patent

From the US filing history. Foreign family members aren’t listed.