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Synthesis method of double-arm intermediate LND1037 for antibody coupling medicine

A technology of LND1037 and antibody-drug coupling, which is applied in peptide preparation methods, chemical instruments and methods, organic chemistry, etc., and can solve the problems of low synthesis yield of intermediate 6, difficult purification, and difficulty in scale-up production

Pending Publication Date: 2021-08-10
LEVENA SUZHOU BIOPHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] However, the synthetic yield of intermediate 6 in the existing synthetic method is low, the purification is difficult, and it is not easy to scale up production

Method used

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  • Synthesis method of double-arm intermediate LND1037 for antibody coupling medicine
  • Synthesis method of double-arm intermediate LND1037 for antibody coupling medicine
  • Synthesis method of double-arm intermediate LND1037 for antibody coupling medicine

Examples

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Embodiment 1

[0055] This example provides a method for synthesizing the two-arm intermediate LND1037 for antibody-drug conjugates, including the following steps.

[0056] Synthesis of LND1037-1

[0057] Fmoc-ADE (100g, 0.306mol, 1eq) and DNPC (186g, 0.612mmol, 2eq) were dissolved in 1L DMF, DIPEA (3.92g, 30.4mmol, 0.1eq) was added, stirred at room temperature for 16 hours, TLC showed that the raw material reacted Complete, add 5L of 5% citric acid aqueous solution to the reaction solution, extract three times with 5L ethyl acetate respectively, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, and purify through a silica gel column. The mobile phase is ethyl acetate:petroleum ether=30: 70, to obtain LND1037-1 (167 g, yield 84%).

[0058] Synthesis of LND1037-4

[0059] BCNOH (100g, 0.666mol, 1eq) was dissolved in dichloromethane (2L), nitrogen was replaced twice, chlorosulfonyl isocyanate (94g, 0.666mol, 1eq) was added, and stirred at room temperature for 15...

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Abstract

The invention provides a synthesis method of a double-arm intermediate LND1037 for an antibody coupling drug. The synthesis method comprises the following steps: preparing LND1037-1 by taking Fmoc-ADE, di(p-nitrobenzene)carbonate and N, N-diisopropylethylamine as raw materials; preparing LND1037-4 by taking BCNOH, chlorosulfonyl isocyanate, triethylamine, diglycolamine, p-nitrophenyl chloroformate and triethylamine as raw materials; preparing Fmoc-LND1024 by taking VC1003, MMAE, 1-hydroxybenzotriazole and DIPEA as raw materials; preparing LND1024 by taking Fmoc-LND1024 as a raw material; preparing LND1037-7 by taking LND1024, LND1037-1, N, N-diisopropylethylamine, 1-hydroxybenzotriazole and diethylamine as raw materials; taking LND1037-4, LND1037-7, N, N-diisopropylethylamine and 1-hydroxybenzotriazole as raw materials, and preparing to obtain the double-arm intermediate LND1037 used for the antibody coupling medicine. The synthesis method disclosed by the invention is high in yield and easy for large-scale production.

Description

technical field [0001] The invention relates to a synthesis method of a double-arm intermediate LND1037 used for antibody-coupled drugs, and belongs to the technical field of medicinal chemistry. Background technique [0002] LND1037 (structure below) is a novel double-arm intermediate, a linker connects two cytotoxins, which can increase the drug loading capacity of the antibody. [0003] [0004] The synthetic method of existing LND1037 is as follows: [0005] [0006] However, the synthesis yield of intermediate 6 in the existing synthesis method is low, the purification is difficult, and it is not easy to scale up production. Contents of the invention [0007] In order to solve the above-mentioned technical problems, the object of the present invention is to provide a method for synthesizing the double-arm intermediate LND1037 with high product yield and easy scale-up production. [0008] In order to achieve the above technical purpose, the present invention pr...

Claims

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Application Information

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IPC IPC(8): C07K5/062C07K1/02C07K1/20
CPCC07K5/06052
Inventor 郭茂君李海泓王相明仇为人许喆
Owner LEVENA SUZHOU BIOPHARMA CO LTD
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