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ADC linker preparation method

A compound and reaction technology, applied in the field of compound preparation, can solve the problems such as the few records of ADClinker preparation methods, and achieve the effects of expanding production, simple and easy production methods, and reducing side reactions

Active Publication Date: 2021-10-22
成都普康唯新生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] At present, the technical route generated by ADC linker focuses on the overall ADC drug, but there are few records on the preparation method of ADC linker

Method used

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Examples

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preparation example Construction

[0053] A preparation method of ADC linker, it comprises the following steps:

[0054] 1) With A as raw material, with copper acetate as catalyst, through N 2 Add Pb(OAc) after replacement 4 , and then prepare compound B through heating reaction;

[0055] 2) Compound B, C and PPTS were added to DCM, and compound D was prepared after reflux overnight;

[0056]3) Add compound D in DMF, add DBU after stirring and dissolving, and remove Fmoc by stirring to obtain a solution containing E; add F, DIEA, HATU in DMF, add the solution containing E after stirring and continue to stir the reaction; Quenching the reaction, extracting, washing, drying, and concentrating under reduced pressure to obtain a creamy substance, then heating, stirring and washing, adding methyl tert-butyl ether, cooling down to crystallize, and drying to obtain G;

[0057] 4) Add DMF and Pd / C to compound G, hydrogenolyze under hydrogen atmosphere, the product is crystallized in DMF, after the reaction is comple...

Embodiment 1

[0120] A kind of preparation method of compound B, its reaction formula is,

[0121]

[0122] The method includes the following steps:

[0123] 1) Add 150gA and 20% (Cu(OAc) 2 With the molar percentage of A, the same below) Cu(OAc) 2 , N 2 Add 262.5gPb(OAc) after replacement 4 , heating the reaction at 65°C, and monitoring the completion of the reaction by TLC;

[0124] 2) Suction filtration after cooling to room temperature, the solid was washed and filtered with ethyl acetate, and the filtrate was concentrated under reduced pressure to obtain a blue oily substance;

[0125] 3) After dissolving the material obtained in the previous steps with ethyl acetate, then use saturated NaHCO 3 Washed twice with aqueous solution and once with saturated brine, Na 2 SO 4 as a desiccant to dry it;

[0126] 4) Concentrate under reduced pressure the material obtained after drying in step 3) to the quality of A, place it for crystallization, and obtain 77.8 g of solid B after suction...

Embodiment 2

[0136] A kind of preparation method of substance D, its reaction formula is,

[0137]

[0138] 1) Add 121.5 grams of B, 219.1 grams of C, 20% (the molar percentage of PPTS and B, the same below) PPTS to 1.4 LDCM, reflux overnight at 45°C, wash with brine three times, and then Na 2 SO 4 Use it as a desiccant to dry it, dissolve it at 45°C and filter it while it is hot.

[0139] 2) After the dried substance was concentrated under reduced pressure, ethyl acetate was added, dissolved at 55°C, crystallized and filtered, cooled to normal temperature and crystallized, repeated twice and then dried to obtain compound D81g. After calculation, The yield thereof was 52%.

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Abstract

The invention relates to an ADC linker preparation method, which comprises: 1) using A as a raw material, using copper acetate as a catalyst, carrying out N2 replacement, adding Pb (OAc) 4, and carrying out a heating reaction to obtain B; 2) adding a compound B, a compound C and PPTS into DCM, and performing reflux overnight to obtain D; (3) adding a compound D into DMF (Dimethyl Formamide), stirring and dissolving, adding DBU, stirring and removing Fmoc to obtain a solution containing E; adding F, DIEA and HATU into DMF, adding the solution containing E after stirring, continuing the reaction, and obtaining G; 4) adding DMF (Dimethyl Formamide) and Pd / C into the compound G, carrying out hydrogenolysis in a hydrogen atmosphere, and sequentially carrying out operations such as crystallization and the like on a product in the DMF to obtain H; 5) adding DMF, H, I and DIEA at the same time, adjusting pH after stirring reaction is completed, and obtaining ADC linker through purification. The preparation method is simple and easy to implement and has few impurities, and a high-purity product can be obtained by crystallizing the product finally.

Description

Technical field: [0001] The invention belongs to the technical field of compound preparation, in particular to a preparation method of ADC linker. Background technique: [0002] Antibody-drug conjugates (ADCs), as novel targeted drugs, consist of three parts, in which the linker connects the cytotoxic payload to the mAb and maintains the stability of the ADC in the systemic circulation. In terms of stability, pharmacokinetic and pharmacodynamic properties, and therapeutic window, the chemical properties and binding sites of linkers play a crucial role in ADC performance. [0003] At present, the technical route generated by ADC linker focuses on the overall ADC drug, but there are few records on the preparation method of ADC linker. Therefore, it is very important to further study how to improve the yield, reduce the generation of impurities, and reduce the cost of ADC linker, so as to be more conducive to expanding production and increasing product revenue. Invention con...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/02C07K1/02
CPCC07K7/02
Inventor 罗前东谭永平
Owner 成都普康唯新生物科技有限公司
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