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Improved process for the synthesis of linker-drug vc-seco-duba

A technology for drugs and compounds, applied in the field of synthetic linkers-drug vc-seco-DUBA and its intermediates, can solve the problems of low yield of four-step method and the like

Pending Publication Date: 2020-08-18
БАЙОНДИС Б. В.
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

On an industrial scale, the yield of this four-step process would be even lower

Method used

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  • Improved process for the synthesis of linker-drug vc-seco-duba
  • Improved process for the synthesis of linker-drug vc-seco-duba
  • Improved process for the synthesis of linker-drug vc-seco-duba

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Effect test

Embodiment 1

[0064] The preparation of embodiment 1-methyl CBI-azaindole-benzamide-MOM-Boc-ethylenediamine-D (4)

[0065]

[0066] Methyl CBI-azaindole-benzamide-MOM (1) (1.0 g, 1.75 mmol) was mixed with tetrahydrofuran (THF) (4.5 g) and N,N-dimethylacetamide (DMA) (3.0 g ) in a mixture of 4-nitrophenyl chloroformate (PNP-Cl) (0.43g, 2.12mmol) in triethylamine (Et 3 In the presence of N) (0.55 g, 4.94 mmol), react at a temperature of 0 °C to 6 °C for about 1.5 hours. A slurry comprising methyl CBI-azaindole-benzamide-MOM-PNP (2) was obtained.

[0067] In a second step, (2-((2-(2-hydroxyethoxy)ethyl)amino)ethyl)(methyl)-tert-butylcarbamate (3) (0.58g, 2.19mmol) Dissolved in DMA (1.7 g) and added 1-hydroxybenzotriazole hydrate (HOBt) (0.35 g, 2.28 mmol). The obtained solution was reacted with the slurry for 1.5 hours at 4°C allowing to warm up to 10°C.

[0068] After completion of the reaction, ethyl acetate (EtOAc) (8.8 g) was added to the reaction mixture, and the solution was washed ...

Embodiment 2

[0070] Embodiment 2-Preparation of vc-seco-DUBA

[0071] Preparation of methyl CBI-azaindole-benzamide-ethylenediamine-D hydrochloride (5)

[0072]

[0073] Pass through 15% hydrogen chloride (HCl) (7.5 g) in 1,4-dioxane in the presence of scavengers (triisopropylsilane (0.63 g), water (0.4 g) and methanol (0.3 g)) Removal of methoxymethyl (MOM) and tert-butoxycarbonyl (Boc ). Methyl CBI-azaindole-benzamide-ethylenediamine-D hydrochloride (5) crystallized from the reaction solution as a yellow solid.

[0074] The obtained yellow solid was filtered off, washed with acetone and dried on the filter under nitrogen and vacuum to give pure product (5) (1.0 g, 1.33 mmol; 90% yield, > 90% purity).

[0075] Preparation of vc-seco-DUBA

[0076]

[0077] Methyl CBI-azaindole-benzamide-ethylenediamine- Maleimide-OEG in D hydrochloride (5) (1.0 g, 1.33 mmol) with DMA (17.8 g) 2 - val-cit-PABA-PNP (6) (0.98 g, 1.29 mmol) was reacted in the dark at a temperature of 0° C. allowed ...

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Abstract

The present invention relates to an improved process for the synthesis of linker-drug vc-seco-DUBA and its intermediates, as well as to the use of said improved process in a process for preparing an antibody-drug conjugate comprising the vc-seco-DUBA linker-drug.

Description

technical field [0001] The present invention relates to improved methods for the synthesis of linker-drug vc-seco-DUBA and intermediates thereof, and to methods of preparing antibody-drug conjugates comprising said vc-seco-DUBA linker-drug the use of. Background technique [0002] Duocarmycin is a member of the family of antitumor antibiotics, which includes duocarmycin A, duocarmycin SA, and CC-1065. They are known for their powerful antitumor properties, but are not usually used alone due to their extreme toxicity. Currently, duocarmycin is being explored as a cytotoxic drug in antibody-drug conjugate (ADC). [0003] ADCs have the potential to address the large unmet need for effective new treatments in cancer by targeting highly potent cytotoxic drugs specifically to cancer cells, increasing potency while reducing potentially systemic toxic side effects of small molecule drugs. [0004] One of the key aspects for the future commercial success of ADCs is the method of s...

Claims

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Application Information

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IPC IPC(8): C07D471/04A61K31/437A61P35/00
CPCC07D471/04A61P35/00A61K47/6803A61K47/6855A61K31/437A61K39/3955
Inventor 弗拉迪米尔·亚瑙谢克马丁·卡什
Owner БАЙОНДИС Б. В.
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