Industrialized production method for antibody coupling medicine connexon

A production method and linker technology, applied in the field of preparation of antibody-conjugated drug Adcetris linker, to achieve the effects of mild reaction conditions, simple and easy post-processing operation, and simple and convenient operation method

Pending Publication Date: 2017-02-08
SHANGHAI HAOYUAN MEDCHEMEXPRESS CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] Compound VIII is the linker of the only ADC drug currently on the market,

Method used

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  • Industrialized production method for antibody coupling medicine connexon
  • Industrialized production method for antibody coupling medicine connexon
  • Industrialized production method for antibody coupling medicine connexon

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0058] Example 1: (9H-fluoren-9-yl)methyl ((S)-1-(((S)-1-((4-(((tert-butyldimethylsilyl)oxy) Preparation of methyl)phenyl)amino)-1-oxo-5-ureido-pent-2-yl)amino)-3-methyl-1-oxobutan-2-yl)carbamic acid

[0059]

[0060] Under the protection of nitrogen, compound I (1.08kg, 2.18mol, 1.0eq) and compound IX-1 (517.6g, 2.18mol, 1.0eq) were added to ethyl acetate (20.0L), stirred at room temperature for half an hour to the raw material All dissolved, then ethyl chloroformate (236.6g, 2.18mol, 1.0eq) and ethyl acetate (1.6L) solution of triethylamine (220.6g, 2.18mol, 1.0eq) were added to the reaction system, dropwise The process temperature is controlled at -5~-15°C. After the dropwise addition, slowly rise to room temperature and continue the reaction until the liquid phase tracking shows that the raw material I in the reaction system disappears, and the reaction is stopped. After the reaction was terminated, the solution was removed under normal pressure, the remaining solid w...

Embodiment 2

[0062] Example 2: (S)-2-((S)-2-amino-3-methylbutanamido)-N-(4-(((tert-butyldimethylsilyl)oxy) Preparation of Methyl)phenyl)-5-ureidopentanamide

[0063]

[0064] Add compound X-1 (3.44kg, 4.8mol, 1.0eq) to N,N-dimethylformamide (17.2L) at room temperature, stir for half an hour until all the raw materials are dissolved, then add diethylamine (700.8g , 9.6mol, 2.0eq), until the liquid phase tracking shows that the raw material X-1 in the reaction system disappears, stop the reaction. After the reaction is stopped, desolventize under normal pressure (spin off 3 / 4 of the total volume of the solution), then add the residue to ethyl acetate (5L), stir until clear, then add petroleum ether dropwise to the system until a white turbid solution appears , then add ethyl acetate back dropwise until just dissolved, leave it open at room temperature for 16-48 hours, solids precipitate out, filter, collect the filter cake and wash with petroleum ether (3L × 2), dry in vacuo to obtain a ...

Embodiment 3

[0066] Example 3: 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-N-((S)-1-(((S)-1-(( Preparation of 4-(hydroxymethyl)phenyl)amino)-1-oxo-5-ureidopent-2-yl)amino)-3-methyl-1-oxobutan-2-yl)hexanamide

[0067]

[0068] Compound XI-1 (269g, 0.55mol, 1.0eq) and compound V (168.1g, 0.55mol, 1.0eq) were added to N,N-dimethylformamide (1L) at room temperature, and stirred at room temperature for half an hour to All the raw materials were dissolved, and then the temperature was raised to 45-50°C and reacted for 4-6 hours to obtain a reaction liquid of the substitute, and the reaction liquid was cooled to -5-0°C and tetramethylammonium fluoride (50.7g, 0.55mol, 1.0eq ) in N,N-dimethylformamide (350 mL) solution, the dropwise addition was completed, and the temperature was raised to room temperature to react until the liquid phase tracking showed that the raw materials in the reaction system disappeared, and the reaction was stopped. After the reaction stopped, water was added to the react...

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PUM

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Abstract

The invention relates to an industrialized production method for preparing an antibody coupling medicine Adcetris connexon. Through a method for protecting a hydroxyl group of a compound IV, the moisture absorption performance is improved, the post-processing operation is simplified, and the product meeting requirements of pharmaceutical-grade raw material drugs is obtained. The method is not only suitable for a small amount of preparation in laboratories but also suitable for large-scale industrial production.

Description

technical field [0001] The invention relates to an industrial production method for preparing an antibody-coupled drug Adcetris linker. The invention belongs to the field of organic synthesis. Background technique [0002] Chemotherapy, as an important cancer treatment, uses cytotoxic agents that may cause serious side effects due to their lack of specificity for tumor cells. Antibody-Drug Conjugate (ADC), as a targeted anti-cancer drug, can perfectly combine monoclonal antibodies and high-efficiency cytotoxins, that is, it makes full use of the targeting properties of monoclonal antibodies and The advantages of strong selectivity; and the advantages of high lethality of cytotoxins on tumor cells are well utilized; at the same time, due to the coupling of cytotoxins and antibodies, the formed drugs have little toxicity to the body and are also very good The defect that a single cytotoxin is highly toxic to the body is solved. [0003] Generally, ADC includes four parts: t...

Claims

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Application Information

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IPC IPC(8): C07K5/033C07K1/06C07K1/02
CPCY02P20/55
Inventor 马涛何运强孙昱飞周治国高强郑保富
Owner SHANGHAI HAOYUAN MEDCHEMEXPRESS CO LTD
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