Processes for preparing phosphorodiamidate morpholino oligomers
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.
1. 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 R 1 is a support-medium,
with a deblocking agent to form the compound of Formula (II):
wherein R 1 is a support-medium;
(b) contacting the compound of Formula (II) with compound (B):
to form a compound of Formula (III):
wherein R 1 is a support-medium;
(c) contacting the compound of Formula (III) with a deblocking agent to form a compound of Formula (IV):
wherein R 1 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 R 1 is a support-medium;
(e) contacting the compound of Formula (V) with a deblocking agent to form a compound of Formula (VI):
wherein R 1 is a support-medium;
(f) contacting the compound of Formula (VI) with compound of Formula (T):
to form a compound of Formula (VII):
wherein R 1 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 R 2 is, independently for each compound of Formula (VIII), selected from the group consisting of:
wherein, for each iteration from 1 to 23, R 2 is:
Iteration No.
R 2
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 R 1 is a support-medium,
wherein R 2 is, independently for each occurrence, selected from the group consisting of:
and
wherein R 2 is at each position from 1 to 25 and 5′ to 3′:
Position No.
5′ to 3′
R 2
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 R 1 is a support-medium,
wherein R 2 is, independently for each occurrence, selected from the group consisting of:
and
wherein R 2 is at each position from 1 to 25 and 5′ to 3′:
Position No.
5′ to 3′
R 2
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 R 2 is, independently for each occurrence, selected from the group consisting of:
and
wherein R 2 is at each position from 1 to 25 and 5′ to 3′:
Position No.
5′ to 3′
R 2
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).
2. The process of claim 1 , wherein step (d), step (f) or step (g2) further comprises contacting the compound of Formula (IV), Formula (VI), or the compound formed by the immediately prior step, respectively, with a capping agent.
3. The process of claim 1 , wherein the deblocking agent used in each step is cyanoacetic acid.
4. The process of claim 3 , wherein the halogenated acid is selected from the group consisting of chloroacetic acid, dichloroacetic acid, trichloroacetic acid, fluoroacetic acid, difluoroacetic acid, and trifluoroacetic acid.
5. The process of claim 1 , wherein the support-medium comprises a material selected from the group consisting of glass, modified or functionalized glass, plastics, polysaccharides, nylon or nitrocellulose, ceramics, resins, silica or silica-based materials, carbon, metals, and optical fiber bundles.
6. The process of claim 1 , wherein the oligomeric compound of Formula (G) is an oligomeric compound of Formula (XII):
7. A compound of Formula (IX):
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is a support-medium, and
R 2 is, independently at each occurrence, selected from the group consisting of:
and
wherein R 2 is at each position from 1 to 25 and 5′ to 3′:
Position No.
5′ to 3′
R 2
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.
8. The compound of claim 7 , wherein the compound of Formula (IX) is of Formula (IXa):
or a pharmaceutically acceptable salt thereof, wherein
R 1 is a support-medium, and
R 2 is, independently at each occurrence, selected from the group consisting of:
and
wherein R 2 is at each position from 1 to 25 and 5′ to 3′:
Position No.
5′ to 3′
R 2
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.
9. The compound according to claim 7 , wherein the support-medium comprises polystyrene with 1% crosslinked divinylbenzene.
10. A compound of Formula (XI):
or a pharmaceutically acceptable salt thereof, wherein:
R 2 is, independently at each occurrence, selected from the group consisting of:
and
wherein R 2 is at each position from 1 to 25 and 5′ to 3′:
Position No.
5′ to 3′
R 2
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.
11. The compound of claim 10 , wherein the compound of Formula (XI) is of Formula (XIa):
or a pharmaceutically acceptable salt thereof, wherein
R 2 is, independently at each occurrence, selected from the group consisting of:
and
wherein R 2 is at each position from 1 to 25 and 5′ to 3′:
Position No.
5′ to 3′
R 2
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.
12. The process of claim 5 , wherein the support-medium comprises plastics selected from the group consisting of acrylics, polystyrene, copolymers of styrene and other materials, polypropylene, polyethylene, polybutylene, and polyurethanes.
13. The process of claim 5 , wherein the support-medium comprises polystyrene with 1% crosslinked divinylbenzene.