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Synthetic method for high-purity biapenem

A biapenem and synthesis method technology, applied in the field of pharmaceutical synthesis, can solve the problems of increasing the degradation of biapenem, prolonging the time of biapenem, and poisoning zinc powder, so as to reduce the content of impurities, improve the purity of products, increase the The effect of water solubility

Inactive Publication Date: 2016-04-13
SHANDONG LUKANG BIOLOGICAL PESTICIDES CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] 1. The purity of the docking material is not high, and some impurities poison the zinc powder, making the amount of zinc powder uncontrollable; the speed of reaction start-up is uncontrollable; the formation of impurities is uncontrollable
[0010] 2. It is necessary to distill off the organic solvent in one step, prolong the time of biapenem in the water phase, greatly increase the degradation of biapenem, and make the product purity and yield lower

Method used

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  • Synthetic method for high-purity biapenem
  • Synthetic method for high-purity biapenem
  • Synthetic method for high-purity biapenem

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Add 16g of MAP and 6.5g of biapenem side chains into the reaction flask, add 90ml of acetonitrile, 25ml of acetone and 15ml of DMF, add 7.1g of N,N-diisopropylethylamine at 0°C, wait for crystals to precipitate, and grow the crystals 1h, filter with suction, add 150ml of dichloromethane to the filter cake and stir wash for 1h, filter with suction, and dry;

[0036] Add 50ml, 50% acetonitrile aqueous solution to the filter cake, dissolve at a temperature of 25°C for 30 minutes, remove insoluble matter by suction filtration, and then wash with 10ml, 50% acetonitrile aqueous solution; distill the acetonitrile aqueous solution in a 30°C water bath to remove acetonitrile, then add 180ml of acetone to crystallize, A large amount of white crystals were precipitated, and the crystals were grown for 30 minutes, cooled to 0°C and grown for 30 minutes, filtered by suction, and dried to obtain 11.8 g of biapenem docking compound, which was white;

[0037] Prepare 150ml*2 of 0.30NpH...

Embodiment 2

[0040] Add 16g of MAP and 6.5g of biapenem side chains into the reaction flask, add 150ml of acetonitrile, add 7.1g of N,N-diisopropylethylamine at 0°C, wait for crystals to precipitate, grow the crystals for 1 hour, and filter with suction. Add the filter cake to 150ml of dichloromethane and stir wash for 1h, filter with suction, and dry;

[0041] Add 40ml of 50% acetonitrile aqueous solution to the filter cake, dissolve at 30°C for 20min, add 1g of activated carbon for decolorization for 10min, remove insoluble matter by suction filtration, wash with 10ml of 50% acetonitrile aqueous solution; distill the acetonitrile aqueous solution in a 30°C water bath to remove acetonitrile and form a paste ; Add 100ml of pentanone, a large amount of white crystals precipitated, the temperature was lowered to 5°C to grow the crystals for 30 minutes, suction filtered, dried, and 11.7g of biapenem docking compound was obtained;

[0042] Prepare 0.20NpH=4.9EDTA-citrate solution 200ml*2, add ...

Embodiment 3

[0045]Add 16g of MAP and 6.5g of biapenem side chains into the reaction flask, add 65ml of acetonitrile, 45ml of methanol and 25ml of DMF, add 7.1g of N,N-diisopropylethylamine at 0°C, wait for crystals to precipitate, and grow the crystals 1h, filter with suction, add 150ml of dichloromethane to the filter cake and stir wash for 1h, filter with suction, and dry;

[0046] Add 55ml of 50% acetonitrile aqueous solution to the filter cake, dissolve at 50°C for 20min, add 1g of activated carbon for decolorization for 10min, remove insoluble matter by suction filtration, wash with 10ml of 50% acetonitrile aqueous solution, distill the acetonitrile aqueous solution in a 30°C water bath to remove acetonitrile, and form a paste ; Add 150ml of acetone, a large amount of white crystals precipitated, cooled to 3°C to grow the crystals for 30 minutes, suction filtered, dried, and 11.9g of biapenem docking compound was obtained;

[0047] Prepare 0.25NpH=5.2 EDTA acid-EDTA sodium solution 2...

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Abstract

The invention discloses a synthetic method for high-purity biapenem and belongs to the technical field of medicine synthesis. The synthetic method comprises dropwise adding ethyldiisopropylamine into a pure acetonitrile or mixed acetonitrile solvent system containing a mother nucleus MAP (beta-Methyl vinyl phosphate) and a single-sulfur side chain, so as to prepare a crude product biapenem docking substance, and then performing water-phase refining and protective-group removal, so as to obtain the high-purity biapenem. By adding the water-phase refining step before protective-group removal of the crude product biapenem docking substance, sulfur-containing impurities are completely removed, and influence of the sulfur-containing impurities on zinc powder is eliminated, and also the biapenem docking substance purity is improved, salt content in the biapenem docking substance is reduced, and the water solubility of the biapenem docking substance is increased. A zinc-powder control model can well solve the zinc-powder quantity problem, enables a zinc-powder protection agent reaction to be controllable, enables the main reaction to be performed completely, and reduces impurity content. By removing the protective group in a buffer system, degradation of biapenem in the reaction is reduced, and product impurity is improved.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical synthesis, and in particular relates to a method for synthesizing high-purity biapenem. Background technique [0002] Biapenem is a new type of 1β-methyl carbapenem antibiotics with a broad antibacterial spectrum and strong antibacterial activity against Gram-positive bacteria, negative bacteria and anaerobic bacteria, and does not require the combination of enzyme preparations , high stability to β-lactamase; in addition, almost no nephrotoxicity, almost no central nervous toxicity, and small side effects. [0003] Biapenem is an injection preparation developed by Lederle Corporation of Japan and Cyamide Corporation of the United States. It was approved for marketing in Japan in March 2002. In 2008, two domestic manufacturers obtained approval for the preparation and began to sell it. [0004] For the synthesis of biapenem, the currently used method is to add N,N-diisopropylethylamine dro...

Claims

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Application Information

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IPC IPC(8): C07D519/06
CPCY02P20/55C07D519/06
Inventor 廖韦红纪衍英
Owner SHANDONG LUKANG BIOLOGICAL PESTICIDES CO LTD