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 (C):
or a pharmaceutically acceptable salt thereof,
wherein the process comprises the sequential steps of:
(a) contacting a compound of Formula (A1):
wherein 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 R 1 is a support-medium;
(b) contacting the compound of Formula (II) with a compound of Formula (A2):
wherein R 3 is selected from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl;
to form a compound of Formula (A3):
wherein R 1 is a support-medium, and R 3 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 R 1 is a support-medium;
(d) contacting the compound of Formula (IV) with a compound of Formula (A4):
wherein R 3 is selected from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl, and R 4 is:
to form a compound of Formula (A5):
wherein R 1 is a support-medium, R 3 is selected from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl, and
R 4 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 R 3 is selected from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl, and R 4 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, R 1 is a support-medium, R 3 is selected from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl, and R 4 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, R 1 is a support-medium, and R 4 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 R 4 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).
2. The process of claim 1 , wherein the compound of Formula (A4) is of Formula (A4a):
wherein:
R 3 is selected from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl, and
R 4 is:
3. The process of claim 1 , wherein the compound of Formula (A5) is of Formula (A5a):
wherein:
R 1 is a support-medium,
R 3 is selected from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl, and
R 4 is:
4. The process of claim 1 , wherein the compound of Formula (A8) is of Formula (A8a):
wherein:
R 3 is selected from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl, and
R 4 is, as per the oligomeric compound of Formula (C) selected from the group consisting of:
5. The process of claim 1 , wherein the compound of formula (A9) is of Formula (A9a):
wherein:
n is 22,
R 1 is a support-medium,
R 3 is selected from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl, and
R 4 is, as per the oligomeric compound of Formula (C), selected from the group consisting of:
6. The process of claim 1 , wherein the compound of Formula (A10) is of Formula (A10a):
wherein:
n is 22,
R 1 is a support-medium, and
R 4 is, as per the oligomeric compound of Formula (C), selected from the group consisting of:
7. The process of claim 1 , wherein the compound of Formula (A11) is of Formula (A11a):
wherein:
n is 22, and
R 4 is, as per the oligomeric compound of Formula (C), selected from the group consisting of:
8. The process of claim 1 , wherein the oligomeric compound of Formula (C) is an oligomeric compound of Formula (XII):
or a pharmaceutically acceptable salt thereof.
9. The process of claim 1 , wherein R 3 is, at each occurrence, trityl.
10. The process of claim 1 ,
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 (D):
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 (F):
to form a compound of Formula (VII):
wherein R 1 is a support-medium;
(g) performing 20 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, as per the oligomeric compound of Formula (C), selected from the group consisting of:
wherein, for each iteration from 1 to 20, R 2 is:
Iteration No.
R 2
1
PA
2
T
3
DPG
4
PC
5
PC
6
PA
7
T
8
PC
9
PC
10
T
11
DPG
12
DPG
13
PA
14
DPG
15
T
16
T
17
PC
18
PC
19
T
20
DPG
to form a compound of Formula (IX):
wherein R 1 is a support-medium,
wherein R 2 is at each position from 1 to 22 and 5′ to 3′:
Position No. 5′ to 3′
R 2
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
(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 at each position from 1 to 22 and 5′ to 3′:
Position No. 5′ to 3′
R 2
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
(i) contacting the compound of Formula (X) with a cleaving agent to form a compound of Formula (XI):
wherein R 2 is at each position from 1 to 22 and 5′ to 3′:
Position No. 5′ to 3′
R 2
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
and
(j) contacting the compound of Formula (XI) with a deprotecting agent to form the oligomeric compound of Formula (C).
11. The process of claim 10 , 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.
12. The process of claim 1 , wherein the deblocking agent used in each step is halogenated acid or cyanoacetic acid.
13. The process of claim 12 , wherein the halogenated acid is selected from the group consisting of chloroacetic acid, dichloroacetic acid, trichloroacetic acid, fluoroacetic acid, difluoroacetic acid, and trifluoroacetic acid.
14. 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.
15. A compound of Formula (IX):
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is a support-medium, and
R 2 is at each position from 1 to 22 and 5′ to 3′:
Position No. 5′ to 3′
R 2
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
16. The compound of claim 15 , 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 at each position from 1 to 22 and 5′ to 3′:
Position No. 5′ to 3′
R 2
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
17. A compound of Formula (X):
or a pharmaceutically acceptable salt thereof, wherein
R 1 is a support-medium, and
R 2 is at each position from 1 to 22 and 5′ to 3′:
Position No. 5′ to 3′
R 2
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
18. The compound of claim 17 , wherein the compound of Formula (X) is of Formula (Xa):
or a pharmaceutically acceptable salt thereof, wherein
R 1 is a support-medium, and
R 2 is at each position from 1 to 22 and 5′ to 3′:
Position No. 5′ to 3′
R 2
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
19. The compound according to claim 15 , wherein the support-medium comprises polystyrene with 1% crosslinked divinylbenzene.
20. A compound of Formula (XI):
or a pharmaceutically acceptable salt thereof, wherein:
R 2 is at each position from 1 to 22 and 5′ to 3′:
Position No. 5′ to 3′
R 2
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
21. The compound of claim 20 , wherein the compound of Formula (XI) is of Formula (XIa):
or a pharmaceutically acceptable salt thereof, wherein
R 2 is at each position from 1 to 22 and 5′ to 3′:
Position No. 5′ to 3′
R 2
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