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Method for preparing intermediate used for synthesizing bortezomib

A technology for bortezomib and intermediates, applied in the field of organic chemical synthesis, can solve problems such as difficulty in obtaining high optical purity bortezomib, inability to meet large-scale production requirements, and difficulty in obtaining raw materials, and achieve remarkable effects and economic practicability. , mild reaction conditions, simple post-processing effect

Active Publication Date: 2013-04-17
重庆瑞泊莱制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although this method solves the disadvantages that the raw materials in the above two routes are not easy to get and expensive, and has the advantages of easy to get raw materials, low price, mild reaction conditions, etc., but this route is very easy to produce double bond shift when imine is formed. However, racemization occurs due to the side reaction, and it is difficult to obtain the final product bortezomib with high optical purity due to the side reactions. It needs to be separated by silica gel column chromatography to obtain bortezomib with optical purity that meets the requirements. Therefore, this route cannot meet the requirements. Large-scale production requirements

Method used

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  • Method for preparing intermediate used for synthesizing bortezomib
  • Method for preparing intermediate used for synthesizing bortezomib
  • Method for preparing intermediate used for synthesizing bortezomib

Examples

Experimental program
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Effect test

Embodiment 1

[0035] Embodiment 1: Synthesis of (1-hydroxyl-3-methyl) butyl-pinacol borate III

[0036]

[0037] Add 43g (0.5mol) of 3-methylbutyraldehyde I, 2.5g (0.025mol) of cuprous chloride and 254g (1mol) of double pinacol borate II into a 1L four-necked flask, add 750ml of benzene, and reflux After reacting for 4 hours, the solvent was evaporated to dryness under reduced pressure to obtain 100.6 g of oily crude product III with a molar yield of 94%. The product was directly put into the next reaction without purification.

Embodiment 2

[0038] Embodiment 2: Synthesis of (1-hydroxyl-3-methyl) butyl-pinacol borate III

[0039]

[0040] Add 43g (0.5mol) 3-methylbutyraldehyde I, 5g (0.025mol) copper acetate and 381g (1.5mol) double pinacol borate II into a 2L four-necked flask, add 1L dichloromethane, and reflux After reacting for 6 hours, the solvent was evaporated to dryness under reduced pressure to obtain 96.5 g of oily crude product III with a molar yield of 90%, which was directly put into the next reaction without purification.

Embodiment 3

[0041] Embodiment 3: Synthesis of (1-hydroxyl-3-methyl) butyl-pinacol borate III

[0042]

[0043] Add 43g (0.5mol) 3-methylbutyraldehyde I, 3.6g (0.025mol) cuprous bromide and 191g (0.75mol) double pinacol borate II into a 1L four-necked flask, add 600ml of benzene, The reaction was refluxed for 8 hours, and the solvent was evaporated to dryness under reduced pressure to obtain 94 g of oily crude product III with a molar yield of 88%. The product was directly put into the next reaction without purification.

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Abstract

The invention discloses a method for preparing an intermediate used for synthesizing bortezomib, comprising the following steps of: carrying out an addition reaction on 3-methyl butyraldehyde and bis(pinacolaton)diboron, then carrying out sulfonylation or halogenating reaction, carrying out an amination reaction with R-(+)-1-phenylethylamine, carrying out catalytic hydrogenation a debenzylation reaction, and finally carrying out enantiomer resolution. Compared with the prior art, the preparation method of the R-(1-amino-3-methyl) butyl boronic acid pinacol cyclic ester intermediate, provided by the invention, has the advantages that raw materials are cheap and easy to get, operation is easy, reaction conditions are mild and optical purity is high, and especially post-processing is simple and the high-optical-purity bortezomib can be easily obtained without column chromatography separation when the intermediate prepared by the invention is used for synthesizing the bortezomib, so that industrial production requirement of the bortezomib is met and the preparation method provided by the invention has obvious effect and economic practicability.

Description

technical field [0001] The invention relates to a method for preparing an intermediate used for synthesizing bortezomib: R-(1-amino-3-methyl)butyl pinacol borate, which belongs to the technical field of organic chemical synthesis. Background technique [0002] Bortezomib (also known as Velcade), the English name is Bortezomib, the chemical name is: [(1R)-3-methyl-1-[[(2S)-1-oxo-3-phenyl-2-[( Pyrazinyl)amino]propyl]amino]butyl]-boronic acid, its chemical structural formula is as follows: [0003] Bortezomib was first discovered in early clinical trials in patients with relapsed multiple myeloma and ineffectiveness to other therapies. Since phase II clinical trials can significantly improve the condition of patients, it was quickly approved by the US Food and Drug Administration. And officially listed in May 2003. Bortezomib is the first new drug approved for the treatment of multiple myeloma in the past ten years, and it is also the first cancer drug that targets protease...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F5/02
Inventor 高河勇陈琳李长文
Owner 重庆瑞泊莱制药有限公司
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