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Method for preparing bortezomib with (one)-cypress camphor serving as chiral auxiliary reagent

A chiral adjuvant, bortezomib technology, applied in the production of bulk chemicals, peptides, etc., can solve the problems of difficult recovery, expensive pinanediol, high production cost, etc., to reduce production costs and facilitate The effect of recycling

Inactive Publication Date: 2013-01-30
朱锦桃 +3
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But the price of pinanediol is expensive; and recovery is difficult
The above problems make the traditional process production cost high

Method used

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  • Method for preparing bortezomib with (one)-cypress camphor serving as chiral auxiliary reagent
  • Method for preparing bortezomib with (one)-cypress camphor serving as chiral auxiliary reagent

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] Add (-)-cedarediol (24g, 100mmol) and 200ml of petroleum ether (60-90°C) into the reaction flask, and dissolve under stirring at room temperature. Then add isobutylboronic acid (100mmol), and stir the reaction at room temperature for 2-4 hours, separate the water layer, dry the organic layer with anhydrous magnesium sulfate, evaporate the solvent under reduced pressure, and perform silica gel column chromatography (petroleum ether). elution) to obtain 30 g of isobutylboronic acid-(-)-cedarediol ester (4) as an oil. The yield is 84%.

Embodiment 2

[0025] Add (-)-cedarediol (24g, 100mmol) and 200ml of dichloromethane into the reaction flask, and dissolve under normal temperature stirring. Then add isobutylboronic acid (100mmol), and stir the reaction at room temperature for 2-4 hours, separate the water layer, dry the organic layer with anhydrous magnesium sulfate, evaporate the solvent under reduced pressure, and perform silica gel column chromatography (petroleum ether). elution) to obtain 28 g of isobutylboronic acid-(-)-cedarediol ester (4) as an oil. Yield 79%.

Embodiment 3

[0027]Add (-)-cedarediol (24g, 100mmol) and 200ml of toluene into the reaction flask, and dissolve with stirring at room temperature. Then add isobutylboronic acid (100mmol), and stir the reaction at room temperature for 2-4 hours, separate the water layer, dry the organic layer with anhydrous magnesium sulfate, evaporate the solvent under reduced pressure, and perform silica gel column chromatography (petroleum ether). elution) to obtain 31 g of isobutylboronic acid-(-)-cedarediol ester (4) as an oil. The yield is 85%.

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Abstract

The invention discloses a method for preparing bortezomib with (one)-cypress camphor serving as a chiral auxiliary reagent. The technological process includes that the (one)-cypress camphor and boronic acids in an organic solvent form boronic acid-(one)-cypress camphor esters; the boronic acid-(one)-cypress camphor esters are condensed and rearranged at a low temperature to obtain 2-chloro isoamyl boronic acid-(one)-cypress camphor esters; the 2-chloro isoamyl boronic acid-(one)-cypress camphor esters are aminated by lithium bis (trimethylsilyl) amide and removed protecting groups to obtain (one)-cypress camphor-(R)-1-amino-3-isobutyl-borate trifluoroacetic acid salt; the (one)-cypress camphor-(R)-1-amino-3-isobutyl-borate trifluoroacetic acid salt and pyrazine formyl-L-phenylalanine react under the existence of a condensing agent to generate bortezomib-(one)-cypress camphor esters; and the bortezomib-(one)-cypress camphor esters are hydrolyzed to generate bortezomib monomers and further generate bortezomib tripolymers.

Description

technical field [0001] The invention relates to a preparation method of bortezomib, which belongs to the technical field of medicine preparation. Background technique [0002] Bortezomib is a modified dipeptide boronic acid structure, generally referred to as “[(1R)-3-methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinecarbonyl) Amino]propyl]amino]butyl]-boronic acid" (also known as bortezomib monomer, structure 1). However, bortezomib monomer is unstable in its pure form and easily loses water to form a stable ring boronic acid structure (bortezomib trimer, structure 2). The bortezomib trimer functions in pharmacological states or in aqueous (or alcohol / water) systems by releasing bortezomib monomers (1) through hydration equilibrium. Referring to foreign practice, the stable form of bortezomib trimer (2), which is a dipeptide boronic acid structure, is the appropriate raw material for bortezomib. [0003] Chemical Structure: [0004] [0005] Bortezomib is a new type of ant...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K5/078
CPCY02P20/55
Inventor 朱锦桃朱岩平韩启和李杨
Owner 朱锦桃
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