One-pot process for preparing intermediate of antibody-drug conjugate
Inventors
YU, Zhaoxing • LI, Xinfang • LAN, Mingchao • MAO, Xinjie
Assignees
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Publication Number
US-11717575-B2
Publication Date
2023-08-08
Expiration Date
Abstract
The present invention relates to a “one-pot process” for preparing intermediate of antibody-drug conjugate. The preparation process provided by the present invention is simple in operation, and needs no such steps like concentration, washing and filtration of the intermediate reaction liquid, disposal of the organic waste liquid, and packaging and storage of the intermediate. The entire reaction system comprises only one separation and purification treatment, saving costs for labor, equipment, venues, raw materials, etc., and greatly reducing the pollution to the environment. In addition, the “one-pot process” for preparing intermediate of antibody-drug conjugate of the present invention produces the intermediate of antibody-drug conjugate with higher yield. The “one-pot process” for preparing intermediate of antibody-drug conjugate provided by the present invention is more suitable for scale-up production.
Core Innovation
The invention relates to a process for preparing an intermediate of an antibody-drug conjugate comprising a linker portion and a drug portion. The intermediate is Py-MAA-Val-Cit-PAB-D or MC-Val-Cit-PAB-D, in which Py-MAA-Val-Cit-PAB or MC-Val-Cit-PAB serves as the linker portion and D represents a linked drug portion comprising free amino groups. The process is carried out as a one-pot process in which two steps are carried out in one system, producing the stated intermediates.
The one-pot reaction route specifies that an organic base 1 and an organic base 2 are each independently one or two of N,N-diisopropylethylamine and pyridine. The process further specifies a triazole catalyst selected from one or more of 1-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazole, and 1-hydroxy-1H-1,2,3-triazole-4-carboxylic acid ethyl ester. The document describes reacting Py-MAA-Val-Cit-PAB-OH or MC-Val-Cit-PAB-OH with bis(4-nitrophenyl)carbonate (NPC) in the presence of an organic base, then adding additional organic base and the drug portion D in the same reaction system.
The disclosure states that prior two-step or multi-system methods can require extra purification and separation steps, generate more waste, and involve higher drug consumption and cost. The one-pot approach is described as providing fewer purification and separation steps, reduced waste, improved cost efficiency, improved efficiency, simpler operation, and suitability for scale-up production, while producing intermediates corresponding to defined structural formulas (1-22).
Claims Coverage
The provided claim set includes one independent claim. Across the independent claim and its dependent refinements, the coverage focuses on a one-pot, two-step-in-one-system preparation route for antibody-drug-conjugate intermediates with defined linker portions and linked drug portions containing free amino groups, using specified organic bases and selected triazole catalysts.
One-pot two-step preparation in one system for Py-MAA-Val-Cit-PAB-D or MC-Val-Cit-PAB-D
A process for preparing an intermediate of antibody-drug conjugate, where the intermediate is Py-MAA-Val-Cit-PAB-D or MC-Val-Cit-PAB-D with a linker portion (Py-MAA-Val-Cit-PAB or MC-Val-Cit-PAB) and a linked drug portion D comprising free amino groups, wherein the process comprises a reaction route performed as a one-pot process with two steps carried out in one system.
Specified organic base pair from N,N-diisopropylethylamine and pyridine
The one-pot process uses organic base 1 and organic base 2, each independently one or two of N,N-diisopropylethylamine and pyridine.
Triazole catalyst selection from 1-hydroxybenzotriazole-type catalysts
The one-pot process includes a triazole catalyst selected from one or more of 1-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazole, and 1-hydroxy-1H-1,2,3-triazole-4-carboxylic acid ethyl ester.
Linker–drug intermediates with free amino groups for specified cytotoxic drug classes
The linked drug portion D in the intermediate comprises free amino groups and is selected from auristatin cytotoxic agents, anthramycin cytotoxic agents, anthracycline cytotoxic agents, puromycin cytotoxic agents, or camptothecin analogs.
The claims cover a one-pot, two-step-in-one-system method to prepare antibody-drug-conjugate intermediates Py-MAA-Val-Cit-PAB-D or MC-Val-Cit-PAB-D using organic bases selected from N,N-diisopropylethylamine and pyridine, and a triazole catalyst chosen from specified 1-hydroxybenzotriazole-type catalysts, with D comprising free amino groups and being drawn from enumerated cytotoxic agent classes and defined intermediate structures.
Stated Advantages
Fewer purification and separation steps.
Reduced waste.
Improved cost efficiency.
Suitability for scale-up production.
Simpler operation compared with a traditional two-step method.
Reduced consumption of the drug portion by adding the drug only in the final step.
Improved efficiency.
Reduced cost and improved efficiency for large-scale production by avoiding extraction/re-isolation of the PNP intermediate.
Minimizing organic solvent and equipment steps.
Higher final yield for a one-pot process versus a two-step process using the same starting materials.
Cost reduction and suitability for large-scale production.
Documented Applications
Scale-up production.
Preparing an anti-tumor medicament using antibody-drug conjugates.
Preparing antibody-drug conjugates (ADCs) through intermediates comprising a linker portion and a drug portion.
Preparation of antibody-drug conjugate intermediates of the form MC-Val-Cit-PAB-D and Py-MAA-Val-Cit-PAB-D, including intermediates leading to drug portions such as MMAE and other MMAE/MMAF/MMAD and named cytotoxic agent variants.
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