Process for the synthesis of linker-drug vc-seco-DUBA
The compound of formula (II) is an advantageous intermediate for improving the process of synthesizing the linker-drug vc-seco-DUBA, as well as for the overall process for preparing an antibody-drug conjugate comprising the vc-seco-DUBA linker-drug. The methods of making the compound of formula (II) can include recovery of the compound as a solid, such as via crystallization, in high yields and purity.
1. A compound of formula (II):
2. The compound according to claim 1 , wherein the compound is in solid form.
3. The compound according to claim 2 , wherein the solid form is a crystalline solid form.
4. A process for the synthesis of a compound of formula (II):
which comprises reacting a compound of formula (III):
with hydrogen chloride in 1,4-dioxane to form the compound of formula (II).
5. A process for the synthesis of vc-seco-DUBA of formula (I):
which comprises:
reacting a compound of formula (II):
with a compound of formula (VII):
to form vc-seco-DUBA of formula (I).
6. The process according to claim 5 , wherein the reaction of the compound of formula (II) with the compound of formula (VII) is performed in the presence of N,N-diisopropylethylamine.
7. The process according to claim 5 , wherein the reaction of the compound of formula (II) with the compound of formula (VII) is performed in N,N-dimethylacetamide in the presence of N,N-diisopropylethylamine and 1-hydroxybenzotriazole hydrate.
8. The process according to claim 5 , which further comprises forming the compound of formula (II) by reacting a compound of formula (III):
with hydrogen chloride in 1,4-dioxane to form the compound of formula (II).
9. The process according to claim 8 , which further comprises isolating the compound of formula (II) via crystallization.
10. The process according to claim 8 , which further comprises forming the compound of formula (III) by reacting a compound of formula (IV):
with 4-nitrophenyl chloroformate to form a compound of formula (V):
followed by reacting the compound of formula (V) with a compound of formula (VI):
in the presence of 1-hydroxybenzotriazole hydrate to form the compound of formula (III).
11. A process for the synthesis of an antibody-drug conjugate of formula (VIII):
wherein:
Antibody is an antibody or an antigen-binding fragment thereof; and
m is an average drug-to-antibody ratio of from 1 to 8;
which comprises:
(1) reacting a compound of formula (II):
with a compound of formula (VII):
to form vc-seco-DUBA of formula (I):
(2) conjugating vc-seco-DUBA of formula (I) to an antibody, or an antigen-binding fragment thereof, to form an antibody-drug conjugate of formula (VIII).
12. The process according to claim 11 , wherein m is an average drug-to-antibody ratio of from 1 to 6.
13. The process according to claim 11 , wherein m is an average drug-to-antibody ratio of from 1 to 4.
14. The process according to claim 11 , wherein vc-seco-DUBA of formula (I) is conjugated to an anti-HER2 antibody.
15. The process according to claim 14 , wherein the antibody is trastuzumab.
16. The process according to claim 15 , wherein the formed antibody-drug conjugate is of formula (IX):