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Method for preparing ertapenem sodium

A technology of ertapenem sodium and ertapenem, which is applied in the field of preparing carbapenem antibiotics, can solve problems such as low purity, and achieve the effects of improving purity, reducing cost and simplifying operation

Active Publication Date: 2012-09-26
SHENZHEN HAIBIN PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0020] Therefore, the object of the present invention is to provide a new method for preparing ertapenem in order to overcome the shortcomings of high impurity content and low purity of the prepared product

Method used

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  • Method for preparing ertapenem sodium
  • Method for preparing ertapenem sodium
  • Method for preparing ertapenem sodium

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] The ertapenem intermediate with a single protection structure is prepared by reacting 1β-methyl carbapenem bicyclic nucleus MAP with ertapenem side chain ES, and the specific operation steps are as follows:

[0045] A. Pass N through the 500ml four-necked bottle first 2 , add 100ml dimethylformamide (DMF), cool down to 0°C, then add 11.6g MAP, then add 6.48g side chain ES, add dropwise 0.3g tri-n-butylphosphine, stir to dissolve completely, then cool down to -50 °C, 8.1 g of tetramethylguanidine (TMG) was added dropwise, and 0.35 g of 4-N,N-dimethylaminopyridine (DMAP) was added, and the system temperature was maintained at -50 °C to -40 °C for 3 h.

[0046] B. Add 20ml saturated KH dropwise 2 PO 4 Aqueous solution, pH 6.5-7.5, stirred at -40°C for 30 minutes, then heated to 10°C.

[0047] C. Slowly add the solution obtained in step B into 1000ml of 1% hydrochloric acid solution dropwise, so that the pH of the solution is 5.5-5.9, stir for 30 minutes after the additi...

Embodiment 2

[0049] Ertapenem sodium is prepared by catalytically hydrogenating the ertapenem intermediate PE with a single protection structure, and the specific operation steps are as follows:

[0050] A. Add 7g of palladium carbon (7.5%) into 80ml of pure water and stir evenly.

[0051] B. the non-dried PE wet product (water content 65%) that embodiment 1 obtains is dissolved in 210ml tetrahydrofuran (THF), after completely dissolving, joins 60ml water (containing 5g NaHCO 3 , and the MAP molar ratio is 3 equivalents).

[0052] C. Add the solution obtained in step B to the solution obtained in step A, and hydrogenate for 90 minutes at 15-20° C. under 1.7 MPa.

[0053] D. Post-treatment: Pour out the hydrogenation solution, adjust the pH to 5.8 with 20% hydrochloric acid, filter with suction, and wash the filtrate with 300ml of cold CH 2 Cl 2 Extract once, separate the organic phase, filter the water layer, add 3g of activated carbon, stir for 10min, and filter with suction.

[0054]...

Embodiment 3

[0056] The ertapenem intermediate with a single protection structure is prepared by reacting 1β-methyl carbapenem bicyclic nucleus MAP with ertapenem side chain ES, and the specific operation steps are as follows:

[0057] A. Pass N through the 500ml four-necked bottle first 2 , add 100ml of dimethylformamide (DMF), cool down to 0°C, then add 11.6g of MAP, then add 6.48g of side chain ES, add 0.3g of tri-n-butylphosphine, stir to completely dissolve, then cool down to -50°C , add 7.9g of 4-N,N-dimethylaminopyridine (DMAP), keep the system temperature at -50°C to -40°C, and react for 3h.

[0058] B. Add 1.2g of glacial acetic acid dropwise, add 20ml of water, the pH is 6.5-7.5, stir at -40°C for 30min, and heat up to 10°C.

[0059] C. Slowly add the solution obtained in step B into 1000ml 3% KH 2 PO 4 In the aqueous solution, make the pH of the solution 5.5-5.9, stir for 30 minutes after the addition, filter with suction, and wash twice with ice water to obtain 30 g of PE we...

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Abstract

The invention provides a method for preparing ertapenem sodium. In the method provided by the invention, an undried ertapenem intermediate is directly subjected to catalytic hydrogenation, or an ertapenem intermediate which is dried to a water content of 5-65% at 20-30 DEG C is subjected to catalytic hydrogenation, thereby preparing the ertapenem sodium. The method provided by the invention is beneficial to simply and efficiently preparing high-quality ertapenem sodium.

Description

technical field [0001] The invention relates to a method for preparing carbapenem antibiotics, in particular to a method for preparing ertapenem sodium. Background technique [0002] Ertapenem (ertapenem, shown in Formula 1) is a carbapenem antibiotic with broad-spectrum antibacterial properties, jointly developed by Merck and AstraZeneca, and its chemical name is (4R, 5R, 6S)-3-[(3S,5S)-5-[(3-carboxyphenyl)carbamoyl]pyrrolidin-3-yl]sulfur-6-[(1R)-1-hydroxyethyl]-4 -Methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, the specific structural formula is as follows: [0003] [0004] Ertapenem sodium (as shown in Formula 2) is the active ingredient of the ertapenem preparation, and its synthesis has received extensive attention. [0005] [0006] The synthesis of ertapenem sodium is usually carried out according to the following route: [0007] [0008] Specifically, the protected ertapenem intermediate PE' is obtained through the condensation reaction of ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D477/20C07D477/06
CPCC07D477/20C07D477/06C07F7/18
Inventor 任鹏郭靖宁范进伟李伟明守锋刘路陈崇洪
Owner SHENZHEN HAIBIN PHARMA
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