Preparation technology of antibody drug conjugate intermediate by one-pot method

A preparation process and technology for antibody drugs, which are applied in the preparation methods of peptides, anti-tumor drugs, drug combinations, etc., can solve the problems of high material loss, high price, and increased production costs in the production of drugs, so as to reduce production costs and reduce The effect of producing waste liquid and improving production efficiency

Active Publication Date: 2020-09-04
MABPLEX INT LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Multi-system synthesis is also used, and because the drug moiety (such as MMAD / MMAE or MMAF, etc.) connected in the antibody drug conjugate is in the early stage of the reaction (MMAD is added to the reaction system as a reactant when Val-Cit-PAB-MMAD is generated) Rather than the last step to participate in the linking reaction, thus resulting in a higher feed loss of the production drug moiety (such as MMAD / MMAE or MMAF, etc.) through the above-mentioned process, because the drug moiety (such as MMAD / MMAE or MMAF, etc.) connected in the antibody drug conjugate ) are usually more expensive, thus greatly increasing production costs

Method used

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  • Preparation technology of antibody drug conjugate intermediate by one-pot method
  • Preparation technology of antibody drug conjugate intermediate by one-pot method
  • Preparation technology of antibody drug conjugate intermediate by one-pot method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] The preparation of embodiment 1Py-MAA-Val-Cit-PAB-MMAE

[0051] (1) "One pot method" preparation

[0052]

[0053] Add Py-MAA-Val-Cit-PAB-OH (1.8g, 1.0eq) and DMF (40mL) successively to a three-neck round bottom flask, stir until dissolved, then add NPC (882mg, 1.1eq), DIPEA (336mg, 1.0eq), stirred at 24±2°C for 24 hours. Then, DIPEA (672mg, 2.0eq), pyridine (2.3mL), HoBt (351mg, 1.0eq) and MMAE (1.7g, 0.9eq) were added successively to the reaction solution, and the reaction was continued at 24±2°C for 48 hours to prepare the solution The product Py-MAA-Val-Cit-PAB-MMAE (1.9g) was obtained by phase purification, with a purity of 99.84% and a yield of 51.3% [calculation formula: yield=Py-MAA-Val-Cit-PAB-MMAE output ÷(Py -MAA-Val-Cit–PAB-OH dosage ÷702.8×1446.8)×100%].

[0054] (2) "Two-step method" preparation

[0055] Step 1: Preparation of Py-MAA-Val-Cit-PAB-(4-nitrophenyl)carbonate

[0056]

[0057] In the reaction flask, add DMF (40mL), Py-MAA-Val-Ci...

Embodiment 2

[0062] Example 2 Preparation of Py-MAA-Val-Cit-PAB-MMAD

[0063] (1) "One pot method" preparation

[0064]

[0065] Into the reaction bottle, add DMF (4mL), Py-MAA-Val-Cit-PAB-OH (200mg, 1.0eq.), stir to dissolve and add bis(p-nitrophenyl)carbonate (NPC, 95mg, 1.1eq .) and DIPEA (36mg, 1.0eq.), react at 24±2°C for 24 hours, add 1-hydroxybenzotriazole (HoBt, 38mg, 1.0eq.), MMAD (197mg, 0.9eq.) , pyridine (248μL) and DIPEA (73mg, 2.0eq), reacted at 24±2°C for 48 hours, spin-dried, and prepared Py-MAA-Val-Cit-PAB-MMAD (208mg) by HPLC, yield: 48.7%, Purity: 99%.

[0066] (2) "Two-step method" preparation

[0067] Step 1: Preparation of Py-MAA-Val-Cit-PAB-(4-nitrophenyl)carbonate

[0068]

[0069] Into the reaction bottle, add DMF (4mL), Py-MAA-Val-Cit-PAB-OH (200mg, 1.0eq.), stir to dissolve and add bis(p-nitrophenyl)carbonate (NPC, 95mg, 1.1eq .) and DIPEA (36mg, 1.0eq.), reacted at 24±2°C for 24 hours. Ethyl acetate (6 mL) was added to the reaction liquid, and ...

Embodiment 3

[0074] Example 3 Preparation of Py-MAA-Val-Cit-PAB-DX8951

[0075] (1) "One pot method" preparation

[0076]

[0077]Into the reaction bottle, add DMF (4mL), Py-MAA-Val-Cit-PAB-OH (200mg, 1.0eq.), stir to dissolve and add bis(p-nitrophenyl)carbonate (NPC, 95mg, 1.1eq .) and DIPEA (36 mg, 1.0 eq.). React at 24±2°C for 24 hours, add 1-hydroxybenzotriazole (HoBt, 38mg, 1.0eq.), DX8951 (136mg, 0.9eq.), pyridine (248μL) and DIPEA (110mg, 3.0eq), 24± The reaction was continued at 2°C for 48 hours, spin-dried, and Py-MAA-Val-Cit-PAB-DX8951 (123 mg) was prepared by HPLC with a yield of 37.1% and a purity of 97%.

[0078] (2) "Two-step method" preparation

[0079] Step 1: Preparation of Py-MAA-Val-Cit-PAB-(4-nitrophenyl)carbonate

[0080]

[0081] Into the reaction bottle, add DMF (4mL), Py-MAA-Val-Cit-PAB-OH (200mg, 1.0eq.), stir to dissolve and add bis(p-nitrophenyl)carbonate (NPC, 95mg, 1.1eq .) and DIPEA (36mg, 1.0eq.), reacted at 24±2°C for 24 hours. Ethyl acetat...

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Abstract

The invention relates to a method for preparing an antibody drug conjugate intermediate by a one-pot method. A preparation technology comprises the steps of enabling MC-Val-Cit-PAB-OH and bis(4-nitrophenyl) carbonate (NPC) to be in contact for a reaction under the condition of existence of organic alkali, after the reaction is completed, supplementing and adding the organic alkali, 1-hydroxybenzotriazole and a part of drugs D in a reaction system, and performing a reaction to obtain the antibody drug conjugate intermediate. In the whole reaction system, separation and purification treatment isonly performed once, steps of concentration and washing of intermediate reaction liquid, treatment of organic waste liquid, packaging and storage of intermediates, and the like are not needed, and higher yield can be achieved.

Description

technical field [0001] The invention relates to the field of antibody-drug conjugates, in particular to a one-pot preparation process for an antibody-drug conjugate intermediate (ie, a linker part-drug part conjugate). Background technique [0002] Antibody drug conjugate (ADC) is a kind of anti-tumor drug, which includes three components: antibody part (Antibody), linker part (Linker) and drug part (Drug), in which the antibody part and The drug part is connected through the linker part, and its mechanism of action is to use the targeting of the antibody to transport the drug to target cells (such as tumor cells) and then release the drug to achieve the purpose of killing tumor cells. [0003] At present, the most commonly used method for synthesizing antibody-drug conjugates is to covalently link the linker part and the drug part in the liquid phase to form a linker-drug conjugate, and then carry out sulfhydryl or amino coupling with the antibody to form an antibody-drug c...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K5/062C07K1/10A61K47/68A61K31/4745A61P35/00
CPCC07K5/06052A61K47/6851A61K31/4745A61P35/00
Inventor 于昭兴李新芳蓝明超毛新洁
Owner MABPLEX INT LTD
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