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Preparation method of 4-acetyloxy-2-azetidinone compounds

A technology of azetidinone and acetoxy, which is applied in the fields of compounds of group 4/14 elements of the periodic table, chemical instruments and methods, organic chemistry, etc., can solve unfavorable large-scale production, harsh reaction conditions, and reaction condition requirements Harshness and other problems, to achieve the effect of convenient recovery and reuse, mild reaction conditions, easy separation and purification

Inactive Publication Date: 2014-01-29
TAIZHOU VOCATIONAL & TECHN COLLEGE +1
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

During the reaction, Pb(AcO) 4 It has dual functions of catalysis and oxidation. After oxidation, it becomes a lead compound in a low-valence state, which cannot be restored to use. Therefore, this method will bring the problem of heavy metal residues that are difficult to solve, and the Pb 3 o 4 Excessive dosage will lead to serious heavy metal pollution, which is not conducive to environmental protection
In addition, some metal salts or catalysts that are difficult to prepare are also used in the oxidative decarboxylation reaction process. The metal salts or catalysts require harsh reaction conditions (such as anhydrous and oxygen-free conditions), are expensive, and are not easy to recycle and reuse.
In a word, the above method has the disadvantages of harsh reaction conditions, cumbersome treatment process, high cost, and serious environmental pollution, which is not conducive to large-scale industrial production.

Method used

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  • Preparation method of 4-acetyloxy-2-azetidinone compounds
  • Preparation method of 4-acetyloxy-2-azetidinone compounds
  • Preparation method of 4-acetyloxy-2-azetidinone compounds

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] Example 1. (3S,4S)-3-[(R)-1-tert-butyldimethylsiloxyethyl]-4-acetoxy-1-(4-methoxyphenyl)-2 - Synthesis of azetidinone

[0025] Add (3S,4S)-3-[(R)-1-tert-butyldimethylsiloxyethyl]-4-carboxy-1-(4-methoxyphenyl) sequentially into a 500mL three-neck flask -2-azetidinone 37.9g ​​(0.1mol), dichloromethane (200mL), placed under ice bath conditions, then slowly added 23.9g35% peracetic acid (0.11mol), after the peracetic acid was added , and then add 22.7g (0.11mol) of N,N'-dicyclohexylcarbodiimide (DCC), and keep the reaction at 0-5°C for 1-2h. TLC monitors the reaction. After the reaction is over, the reaction mixture is first filtered, and the filtrate is washed with 300 mL of water each time for a total of 3 times. The organic layer obtained after washing with water is washed with saturated NaHCO 3 Wash, anhydrous Na 2 SO 4 After drying, the solvent was evaporated under reduced pressure, and the crude product was recrystallized to obtain 37.7g of a white solid product. ...

Embodiment 2

[0026] Example 2. (3S,4S)-3-[(R)-1-tert-butyldimethylsiloxyethyl]-4-acetoxy-1-(4-methoxyphenyl)-2 - Synthesis of azetidinone

[0027] Add (3S,4S)-3-[(R)-1-tert-butyldimethylsiloxyethyl]-4-carboxy-1-(4-methoxyphenyl) sequentially into a 500mL three-neck flask - 37.9g ​​(0.1mol) of 2-azetidinone, chloroform (150mL), placed in an ice bath, then slowly added 49.4g of 20% peroxyacetic acid (0.13mol), after the peracetic acid was added, then Add 26.8g (0.13mol) of N,N'-dicyclohexylcarbodiimide (DCC), and keep the reaction at 25°C for 1-2h. TLC monitors the reaction. After the reaction is over, the reaction mixture is first filtered, and the filtrate is washed with 300 mL of water each time for a total of 3 times. The organic layer obtained after washing with water is washed with saturated NaHCO 3 Wash, anhydrous Na 2 SO 4 After drying, the solvent was evaporated under reduced pressure, and the crude product was recrystallized to obtain 37.0 g of a white solid product. The struct...

Embodiment 3

[0028] Example 3. (3S,4S)-3-[(R)-1-tert-butyldimethylsiloxyethyl]-4-acetoxy-1-(4-methoxybenzyl)-2 - Synthesis of azetidinone

[0029]Add (3S,4S)-3-[(R)-1-tert-butyldimethylsiloxyethyl]-4-carboxy-1-(4-methoxybenzyl) sequentially into a 500mL three-neck flask -2-azetidinone 39.3g (0.1mol), dichloromethane (200mL), placed under ice bath conditions, then slowly added 26.1g35% peracetic acid (0.12mol), after the peracetic acid was added , and then add 24.8g (0.12mol) of N,N'-dicyclohexylcarbodiimide (DCC), and keep the reaction at 15°C for 1-2h. TLC monitors the reaction. After the reaction is over, the reaction mixture is first filtered, and the filtrate is washed with 300 mL of water each time for a total of 3 times. The organic layer obtained after washing with water is washed with saturated NaHCO 3 Wash, anhydrous Na 2 SO 4 After drying, the solvent was evaporated under reduced pressure, and the crude product was recrystallized to obtain 36.6 g of a white solid product. The...

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Abstract

The invention relates to a preparation method of 4-acetyloxy-2-azetidinone compounds, and is used for solving the problem that the large-scale industrial production cannot be favorably realized because of defects such as severe reaction condition, complex treatment process, high cost, serious environment pollution and the like in the prior art. The method provided by the invention comprises the step of carrying out oxidization deacidification in the existence of a dehydrating agent N, N'-dicyclohexylcarbodiimide and an oxidizing agent peroxyacetic acid by taking 4-carboxyl-2-azetidinone compounds I as raw materials to obtain the 4-acetyloxy-2-azetidinone compounds II. A heavy metal oxidizing agent or catalyst is prevented from being used in the oxidization deacidification process, so that the residue and discharge of heavy metals and environmental pollution caused by the heavy metals are greatly reduced. Byproducts generated in a reaction process can be conveniently recycled, so that the production cost is reduced to the great extent, and the preparation method is more excellent on the aspect of economical efficiency. The method is mild in reaction condition, simple and convenient to operate and suitable for large-scale production; the 4-acetyloxy-2-azetidinone compounds are easy to separate and purify and high in yield.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis and chemical medicine preparation, and relates to a method for preparing 4-acetoxy-2-azetidinone compounds, in particular to a method for preparing penem drug intermediates 4-acetyl The preparation method of oxy-2-azetidinone compound. technical background [0002] The 4-acetoxy-2-azetidinone compound represented by formula II is an important intermediate for the synthesis of penem drugs. Penem drugs are a new group of β-lactam antibiotics, which have the broadest antibacterial spectrum and the strongest antibacterial effect among the antibacterial drugs developed so far. Since the discovery of thiamycin in 1976, the research on penem drugs has made great progress. So far, the penems that have been marketed in the world mainly include imipenem, panipenem, and the United States. Luo Penem (Meropenem), there are many varieties in clinical trials. Therefore, it is of great significance t...

Claims

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Application Information

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IPC IPC(8): C07F7/18
Inventor 管月清周国斌
Owner TAIZHOU VOCATIONAL & TECHN COLLEGE
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