Preparation method of meropenem side chain intermediate mercaptan lactone

A technology of meropenem side chains and body thiols, which is applied in the field of chemical substance preparation, can solve problems such as low yield, high production cost, and long synthetic route, and achieve the effects of high purity, low cost, and improved conversion rate

Inactive Publication Date: 2019-10-29
TIANJIN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Due to the long synthetic route and low yield of only 64.6% in the existing preparation method of meropenem side chain intermediate, the production cost is high, and there is an urgent need for a preparation method of meropenem side chain intermediate with high yield and suitable for industrial production

Method used

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  • Preparation method of meropenem side chain intermediate mercaptan lactone
  • Preparation method of meropenem side chain intermediate mercaptan lactone

Examples

Experimental program
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Effect test

Embodiment 1

[0029] 1) Add 1.8 g of M1 ([(2S,4R)-2-carboxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine)] to 31 mL of dichloromethane, the same below), and keep the liquid temperature at -26 ℃ first drop 0.71g isopropyl chloroformate, then drop 0.78g TEA, react for 15min;

[0030] 2) Add 0.86g MsCl dropwise at -26°C, then add 0.71g TEA dropwise, and react for 26min;

[0031] 3) Add 1.81g Na 2 S·9H 2 O. Dissolve 0.24g of polyethylene glycol 600 and 1.74g of water into a solution, add this solution into the reaction solution at -26°C, raise the temperature from -26°C to 0°C, and keep the heating time for 26min;

[0032]4) After the temperature rise, add deionized water at 0°C for liquid separation, separate the organic phase, raise the temperature of the organic phase to 40°C for reflux reaction, and reflux for 2.5 hours. After the reaction is completed, add 5% Adjust the potassium carbonate solution to pH=9, separate the oil phase 1, continue to adjust the oil phase 1 to pH=1 with 18% hydroch...

Embodiment 2

[0034] 1) Add 1.8g of M1 to 32mL of dichloromethane, keep the liquid temperature at -24°C, add 0.71g of isopropyl chloroformate dropwise, then add 0.77g of TEA dropwise, and react for 19min;

[0035] 2) Add 0.80g MsCl dropwise at -24°C, then add 0.65g TEA dropwise, and react for 30min;

[0036] 3) Add 1.67g Na 2 S·9H 2 O, 0.24g of 18-crown-6 and 1.74g of water were dissolved into a solution, and this solution was added to the reaction solution at -24°C, and the temperature was raised from -24°C to 0°C, and the heating time was maintained for 22 minutes;

[0037] 4) After the temperature rise, add deionized water at 0°C for liquid separation, separate the organic phase, raise the temperature of the organic phase to 38°C for reflux reaction, and reflux for 2.6 hours. After the reaction is completed, add 4% Adjust the potassium carbonate solution to pH=8.3, separate the oil phase 1, and continue to adjust the oil phase 1 to pH=1.1 with 17% hydrochloric acid solution at -1°C, se...

Embodiment 3

[0039] 1) Add 1.8g M1 to 33mL dichloromethane, keep the liquid temperature at -20°C, add 0.85g isopropyl chloroformate dropwise, then add 0.82g TEA dropwise, and react for 17min;

[0040] 2) Add 0.93g MsCl dropwise at -20°C, then add 0.77g TEA dropwise, and react for 22min;

[0041] 3) Add 1.65g Na 2 S·9H 2 O. Dissolve 0.24g tetradecyltrimethylammonium chloride and 1.74g water into a solution, add this solution into the reaction solution at -20°C, raise the temperature from -20°C to 0°C, and keep the heating time for 30min;

[0042] 4) After heating up, add deionized water at 0°C for liquid separation, separate the organic phase, raise the temperature of the organic phase to 39°C for reflux reaction, the reflux reaction time is 2.7h, after the reaction is completed, add 3% carbonic acid at 0°C Adjust the potassium solution to pH=8.7, separate the oil phase 1, continue to adjust the oil phase 1 to pH=1.6 with 16% hydrochloric acid solution at 0°C, separate the oil phase 2, di...

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Abstract

The invention provides a synthesis method of a meropenem side chain intermediate mercaptan lactone with the high yield. The synthesis method comprises the steps that (2S,4R)-2-carboxyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidine) is added into dichloromethane, the liquid temperature is kept at minus 26 DEG C to minus 17 DEG C, isopropyl chlorocarbonate is dropwise added, and then triethylamine is dropwise added to activate carboxyl; MsCl is dropwise added under the same temperature condition, and then triethylamine is dropwise added to activate hydroxyl; a sodium sulfide nonahydrate, a phase transfer catalyst and water are dissolved into a solution, and the solution is added into a reaction solution under the same temperature condition; deionized water is added at 0 DEG C for liquid separation, and an organic phase is separated; the organic phase is subjected to a reflux reaction in a water bath kettle; and alkali is used for adjusting till pH is 8 to 9, an oil phase 1 is separated, the oil phase 1 continues to be adjusted through acid till pH is 1 to 2, an oil phase 2 is separated, after the oil phase 2 is subjected to decompression distillation, oily liquid is obtained, a crystallization solvent is added into the oily liquid, then a low-temperature reaction for bath cooling is conducted, and filtering is conducted to obtain the meropenem side chain intermediate mercaptan lactone.

Description

technical field [0001] The invention relates to the technical field of chemical substance preparation, in particular to a method for preparing a meropenem side chain intermediate (thiol lactone). Background technique [0002] Meropenem is a second-generation carbapenem antibiotic, mainly used for the treatment of severe bacterial infections such as lower respiratory tract infection, abdominal infection, urinary tract infection, etc. All have strong antibacterial activity. And compared with the first-generation carbapenem antibiotics, its nephrotoxicity and central nervous toxicity are less. [0003] At present, such antibiotics are mainly prepared by chemical total synthesis, and the main process includes side chain synthesis and skeleton core synthesis. Among them, the side chain of meropenem is one of the key factors affecting its quality and yield. [0004] The synthetic routes of meropenem side chain intermediates all use trans-4-hydroxy-L-proline as the starting mate...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D495/08
CPCC07D495/08
Inventor 李彬史继星张天永姜爽
Owner TIANJIN UNIV
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