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Method for preparing ring-opening impurity of carbapenems

A carbapenem and antibiotic technology, applied in the field of preparation of ring-opening impurities, can solve problems such as rare reports, and achieve the effects of controlling product quality, short reaction time and simple operation

Active Publication Date: 2015-11-18
山东安弘制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0019] At present, there are few reports on the preparation of ring-opening impurities of carbapenem antibiotics

Method used

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  • Method for preparing ring-opening impurity of carbapenems
  • Method for preparing ring-opening impurity of carbapenems
  • Method for preparing ring-opening impurity of carbapenems

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0056] A method for preparing a ring-opening impurity of meropenem, the ring-opening impurity has the following structure:

[0057]

[0058] Including the following steps:

[0059] Dissolve 0.4g of sodium hydroxide in 100ml of water, cool down to 0-5°C, add meropenem with a net content of 2.0g, keep warm and stir for 2 hours, adjust the pH to 7.0-8.0 with 0.5mol / L hydrochloric acid after the reaction is completed, and freeze-dry. 2.3 g of the ring-opening impurity of meropenem was obtained as a light yellow solid with a purity of 97.4% and a water content of 2.6% by HPLC.

[0060] Wherein, the freeze-drying temperature curve is as follows:

[0061] temperature(°C) Heating time (h) Constant temperature time (h) Vacuum (mtorr) -20 / 40 80～120 10 1 5 80～120 40 1 5 80～120 50 0.5 5 80～120

[0062] The ring-opening impurity of meropenem obtained in Example 1 was detected by NMR, and the results are as follows:

[0063] 1 HNMR (CD...

Embodiment 2

[0065] The preparation method of the ring-opening impurity of meropenem comprises the following steps:

[0066] Dissolve 0.3g of potassium hydroxide in 100ml of water, cool down to 0-5°C, add meropenem with a net content of 2.0g, fully insulate and stir for 2 hours, adjust the pH to 7.0-8.0 with 0.5mol / L hydrochloric acid after the reaction is completed, and freeze-dry. 2.2 g of the ring-opening impurity of meropenem was obtained as a light yellow solid with a purity of 97.5% and a water content of 2.1% by HPLC.

[0067] Wherein, the freeze-drying temperature curve is as follows:

[0068] temperature(°C) Heating time (h) Constant temperature time (h) Vacuum (mtorr) -10 / 20 80～120 10 1 5 80～120 40 1 5 80～120 50 0.5 5 80～120

Embodiment 3

[0070] A method for preparing a ring-opening impurity of ertapenem, the ring-opening impurity has the following structure:

[0071]

[0072] Including the following steps:

[0073]Dissolve 0.4g of sodium hydroxide in 100ml of water, lower the temperature to 0-5°C, add ertapenem with a net content of 2.3g, fully insulate and stir for 2 hours, adjust the pH to 7.0-8.0 with 0.5mol / L hydrochloric acid after the reaction is completed, freeze After drying, 2.6 g of the ring-opening impurity of ertapenem was obtained as a yellow solid with a purity of 96.8% and a water content of 2.8% as detected by HPLC.

[0074] Wherein, the freeze-drying temperature curve is as follows:

[0075] temperature(°C) Heating time (h) Constant temperature time (h) Vacuum (mtorr) -10 / 24 80～120 10 1 5 80～120 40 1 5 80～120 50 0.5 5 80～120

[0076] The ertapenem ring-opening impurity obtained in Example 3 was subjected to nuclear magnetic detection, and t...

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Abstract

The invention relates to a method for preparing a ring-opening impurity of carbapenems. The ring-opening impurity is of a structure represented by formula I. In the formula I, R represents a meropenem side chain, an ertapenem side chain or a doripenem side chain. The method includes the following steps: (1) adding carbapenems into an alkaline solution, stirring and reacting for 1-4 hours; (2) adjusting the pH to 6.0-9.0; (3) freeze-drying the materials to obtain the ring-opening impurity of carbapenems. The method provided by the invention is simple to operate and short in reaction time; the product has the purity of 95% or above and can be directly used as a reference substance for quantitative and qualitative research on the ring-opening impurity of carbapenem products, so that the product quality can be effectively controlled. The formula I is shown in the description.

Description

technical field [0001] The invention relates to a method for preparing ring-opening impurities of carbapenem antibiotics, belonging to the technical field of medicinal chemistry. Background technique [0002] Carbapenems are a class of β-lactam antibiotics developed by American medical researchers in the 1970s, which have strong antibacterial activity against Gram-positive bacteria, negative bacteria, aerobic bacteria and anaerobic bacteria; especially It is 1β-methyl carbapenems, including meropenem (Ⅱ), ertapenem (Ⅲ), doripenem (Ⅳ), etc., stable to β-lactamase and renal dehydropeptide-1 enzyme , so it has a good antibacterial effect on many drug-resistant bacteria. With the emergence of penicillin and cephalosporin-resistant bacteria, carbapenem antibiotics, especially 1β-methyl carbapenem antibiotics, have become one of the most important antibacterial drugs for the treatment of multidrug-resistant bacterial infections. [0003] The structural formula of Meropenem: [...

Claims

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Application Information

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IPC IPC(8): C07D207/24
CPCC07D207/24
Inventor 周存奇符淙淙赵卫良冯宪东
Owner 山东安弘制药有限公司
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