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A kind of preparation method of bortezomib derivative

A technology of bortezomib and derivatives, which is applied in the field of preparation of bortezomib derivatives, can solve the problems of low drug content, decreased activity, and affecting drug stability, and achieve high yield effects

Active Publication Date: 2021-06-25
都创(重庆)医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The impurities contained in the drug are the main factors affecting the purity of the drug. If the drug contains impurities exceeding the limit, it may change the physical and chemical constants, the appearance and properties of the drug, and affect the stability of the drug; the increase of impurities will inevitably increase the content of the drug. Low or reduced activity, significantly increased toxic and side effects

Method used

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  • A kind of preparation method of bortezomib derivative
  • A kind of preparation method of bortezomib derivative
  • A kind of preparation method of bortezomib derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0061] (a) compound 1 is subjected to amidation reaction to prepare compound 2:

[0062] Dissolve (S)-3-phenyl-2-[(pyrazine-2-carbonyl)amino]propanoic acid (compound 1) (5.0 g, 18.4 mmol, 1.0 eq) in dichloromethane (200 mL) and add N,N-Diisopropylethylamine (7.14g, 55.3mmol, 3.0eq) and HATU (10.51g, 27.7mmol, 1.5eq), stirred at room temperature for 30min, then added ammonia water (3.76g, 25% / W, 55.3mmol, 3.0eq), react at room temperature for 2.5 hours. Afterwards, the reaction solution was washed with saturated brine (100mL×3), and then washed with anhydrous Na 2 SO 4 Dry and evaporate under reduced pressure to remove the solvent. The obtained crude product was purified by silica gel column chromatography to obtain 4.3 g of a yellow solid (Compound 2), with a yield of 86.3%.

[0063] (b) Compound 3 is subjected to a methylation reaction to prepare compound 4:

[0064] 3-Hydroxy-3-methylbutanoic acid (compound 3) (20 g, 0.17 mol, 1.0 eq) was dissolved in methanol (200 ...

Embodiment 2

[0076] (a) compound 1 is subjected to amidation reaction to prepare compound 2:

[0077] Dissolve (S)-3-phenyl-2-[(pyrazine-2-carbonyl)amino]propanoic acid (compound 1) (5.0 g, 18.4 mmol, 1.0 eq) in N,N-dimethylformamide (200mL), add triethylamine (5.60g, 55.3mmol, 3.0eq) and EDCl (5.30g, 27.7mmol, 1.5eq), stir at room temperature for 30min, then add ammonia water (3.76g, 25% / W, 55.3 mmol, 3.0eq), reacted at room temperature for 2.5 hours. Afterwards, the reaction solution was washed with saturated brine (100mL×3), and then washed with anhydrous Na 2 SO 4 Dry and evaporate under reduced pressure to remove the solvent. The obtained crude product was purified by silica gel column chromatography to obtain 4.05 g of a yellow solid (Compound 2), with a yield of 81.3%.

[0078] (b) Compound 3 is subjected to a methylation reaction to prepare compound 4:

[0079] 3-Hydroxy-3-methylbutyric acid (compound 3) (20g, 170mmol, 1.0eq) was dissolved in dichloromethane (400mL), triet...

Embodiment 3

[0091] (a) compound 1 is subjected to amidation reaction to prepare compound 2:

[0092] Dissolve (S)-3-phenyl-2-[(pyrazine-2-carbonyl)amino]propanoic acid (compound 1) (5.0 g, 18.4 mmol, 1.0 eq) in N,N-dimethylformamide (200mL), add triethylamine (5.60g, 55.3mmol, 3.0eq) and HATU (10.5g, 27.7mmol, 1.5eq), stir at room temperature for 30min, then add ammonium chloride (1.48g, 27.7mmol, 1.5 eq), reacted at room temperature for 12 hours. Afterwards, the reaction solution was washed with saturated brine (100mL×3), and then washed with anhydrous Na 2 SO 4 Dry and evaporate under reduced pressure to remove the solvent. The obtained crude product was purified by silica gel column chromatography to obtain 4.40 g of a yellow solid (Compound 2), with a yield of 88.3%.

[0093] (b) Compound 3 is subjected to a methylation reaction to prepare compound 4:

[0094] 3-Hydroxy-3-methylbutyric acid (compound 3) (20g, 170mmol, 1.0eq) was dissolved in tetrahydrofuran (200mL), methanol ...

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Abstract

The present invention relates to a preparation method of bortezomib derivatives. The bortezomib derivatives are represented by the following chemical formula 1: the bortezomib derivatives are produced during the synthesis process and / or storage process of bortezomib important impurities. Through the preparation method according to the present application, the above-mentioned bortezomib derivatives can be prepared with a relatively high yield.

Description

technical field [0001] The invention relates to the field of medicine synthesis and analysis, in particular to a preparation method of bortezomib derivatives. Background technique [0002] Bortezomib (PS-341), scientific name: [(1R)-3-methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinecarboxyl)amino ]propyl]amino]butyl]-boronic acid, CAS number: 179324-69-7, molecular formula: C 19 h 25 BN 4 o 4 , molecular weight: 384.24, is an anticancer drug, suitable for the treatment of multiple myeloma and mantle cell lymphoma. Bortezomib is also the first proteasome inhibitor for humans, which inhibits the 20S proteasome (20Sproteasome) by targeting threonine residues, thereby disrupting the cell cycle, inducing apoptosis, and inhibiting nuclear factor NF-κB . Compared with traditional chemotherapy, bortezomib can achieve higher complete remission, can significantly prolong the survival of tumor patients, has definite clinical curative effect, less toxic and side effects, is less likely...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D241/24
CPCC07D241/24
Inventor 单玉庆杜丹凤
Owner 都创(重庆)医药科技有限公司