Preparation of meropenem

A technology for meropenem and compounds, which is applied in the directions of organic chemistry, antibacterial drugs, etc., can solve the problems of inconsistent atomic economy, unfavorable sustainable development, and difficulty in obtaining raw materials, and achieves a shortened production cycle, simplified operation, and simple operation. Effect

Active Publication Date: 2009-01-21
SHENZHEN HAIBIN PHARMA
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  • Abstract
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  • Claims
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AI Technical Summary

Problems solved by technology

[0011] The raw material of route A is easy to obtain and has been widely used at present. However, because the reaction route is long and there are many intermediates, especially chiral intermediates, which need to be separated, it does not meet the requirements of atom economy, which brings some troubles to the operation. The environment has also been polluted; in addition, due to the need to use the compound of noble metal rhodium as catalyst when synthesizing compound (X), along with the shortage and rising price of noble metal rhodium, the preparation cost of this route is also increasing day by day, not a more ideal preparation method
[0012] Although route B is shorter than route A, it is still not a good

Method used

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  • Preparation of meropenem
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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] [Example 1] (3S, 4R)-3-[(1R)-1-tert-butyldimethylsiloxyethyl]-4-[(2R)-2-methyl-1-carboxyethyl] -Synthesis of azetidin-2-one (VI)

[0037] Add 120.70g (1.857mol) of zinc powder to 215ml of anhydrous tetrahydrofuran, heat to boiling with stirring, then add 177.50g (0.618mol) (3S, 4R)-4-acetoxy-3-[(1R) -1-tert-Butyldimethylsiloxyethyl]azetidin-2-one (IV) and 319.50 g (0.909 mol) 3-(2-bromopropyl)-spiro[2,3-dihydro -4H-1,3-benzoxazine-2,1'-cyclohexyl]-4-one (XIV) was dissolved in 640ml of anhydrous tetrahydrofuran to form a mixed solution, the rate of addition was such that the reaction solution did not boil, After adding, reflux for 30 minutes, cool down to room temperature, add 18 g of diatomaceous earth to the reaction mixture, filter the reaction mixture with suction, wash the filter residue with an appropriate amount of tetrahydrofuran, combine the filtrate and the washing liquid, add 215 ml of toluene, and add 710 ml of toluene to the mixture. 2N hydrochloric acid, ...

Embodiment 2

[0042] [Example 2] (3S, 4R)-3-[(1R)-1-(tert-butyldimethylsiloxy)ethyl]-4-{(2R)-2-methyl-1-carbonyl Synthesis of Ethyl-[(2S,4R)-4-(1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonyl)pyrrolidinylthio]}-azetidin-2-one (XVI)

[0043] To 90.3 g (0.30 mol) (3S,4R)-3-[(1R)-1-tert-butyldimethylsiloxyethyl]-4-[(2R)-2-methyl-1- Carboxyethyl]-azetidin-2-one (VI) and 68.1 g (0.33 mol) of dicyclohexanediamine (DCC) dissolved in 400 ml of dichloromethane were added 3 g of 4-dimethylaminopyridine (DMAP). ), then 111.30g (0.315mol) (2S, 4S)-2-dimethylaminocarbonyl-4-mercapto-1-(p-nitrobenzyloxycarbonyl)pyrrolidine (XV) was added dropwise to the reaction solution and dissolved in 500ml The solution in dichloromethane was reacted at room temperature for 12 hours. After the completion of the reaction, filter, collect the filtrate, wash the toluene solution with 600ml of 5% acetic acid solution, saturated sodium bicarbonate solution and saturated brine each once, collect the methylene chloride ...

Embodiment 3

[0044] [Example 3] (3S, 4R)-3-[(1R)-1-(tert-butyldimethylsiloxy)ethyl]-4-{(2R)-2-methyl-1-carbonyl Synthesis of Ethyl-[(2S,4R)-4-(1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonyl)pyrrolidinylthio]}-azetidin-2-one (XVI)

[0045] 100 g (0.332 mol) (0.30 mol) (3S,4R)-3-[(1R)-1-tert-butyldimethylsiloxyethyl]-4-[(2R)-2-methyl at room temperature -1-Carboxyethyl]-azetidin-2-one (VI) and 55.12g (0.349mol) N,N'-carbonyldiimidazole (CDI) were dissolved in 500ml acetone, and then added dropwise to the reaction solution A solution of 111.69g (0.316mol) (2S, 4S)-2-dimethylaminocarbonyl-4-mercapto-1-(p-nitrobenzyloxycarbonyl)pyrrolidine (XV) dissolved in 600ml acetone, react at room temperature for 2.5 hours . After the reaction is completed, acetone is recovered under reduced pressure for recycling, the residual liquid is dissolved in 500 ml of toluene, the toluene solution is washed once with 700 ml of clear water, the toluene layer is collected, dried by adding anhydrous sodium sulf...

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Abstract

The invention provides a method for preparing Meropenem. The method comprises the following steps that: 1) a compound shown in formula (IV) reacts with a compound shown in formula (XIV) to produce a compound with the formula (VI); 2) the compound shown in formula (VI) reacts with a compound shown in formula (XV) to produce a compound shown in formula (XVI), 3) the compound XVI reacts with a compound shown in formula XVII to obtain a compound shown in formula XVIII, 4) the compound shown in formula XVIII is used to prepare a compound shown in the formula XIX; 5) the compound shown in the formula XIX is hydrolyzed to obtain a compound and; and 6) the compound shown in formula XX is deoxidized under the action of catalysts and hydrogen to produce Meropenem shown in formula (I). The method adopted by the invention has shorter synthetic procedures, simplified operation, simple raw material with easy access, and no requirement on the catalyst of precious metal of rhodium.

Description

technical field [0001] The present invention relates to a preparation method of beta-methyl carbapenem antibiotic (Carbapenem), in particular to a preparation method of meropenem (Meropenem). Background technique [0002] Carbapenem represented by meropenem (I) (Sumitomo Pharmaceuticals Co., Ltd.), imipenem (II) (Merck & Co., Inc.) and biapenem (III) (Lederle Ltd.), etc. Since the discovery of alkene antibiotics with their broad-spectrum antibacterial activity, they have been paid much attention. The search for efficient preparation methods has always been one of the research focuses and hotspots in the academic and industrial circles. [0003] [0004] After years of efforts, a variety of methods have been developed for the preparation of β-methylcarbapenem antibiotic parent nucleus. Among them, the representative synthetic routes mainly include the following two: [0005] One is the reaction scheme A (USP4933333) of Sumitomo Pharmaceuticals Co., Ltd., as shown below: ...

Claims

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Application Information

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IPC IPC(8): C07D477/20A61P31/04
CPCC07D477/06C07D477/20A61P31/04
Inventor 卢兆强龙利松陈曦邹灼天张恒利
Owner SHENZHEN HAIBIN PHARMA
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