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Preparation method of ertapenem single sodium salt

A technology of ertapenem and monosodium salt, which is applied in the field of penem medicine synthesis, can solve the problems of product quality decline, unfavorable large-scale production, and yield reduction, and achieve high product quality, reduced impact, and high product quality Effect

Inactive Publication Date: 2017-01-04
SHANGHAI LONGXIANG BIO MEDICINE DEV CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] According to the literature, ertapenem sodium is extremely unstable, and the method of evaporative crystallization will inevitably lead to the decomposition of ertapenem sodium, resulting in a decrease in yield and product quality, and the method of evaporative crystallization is not conducive to large-scale production

Method used

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  • Preparation method of ertapenem single sodium salt
  • Preparation method of ertapenem single sodium salt
  • Preparation method of ertapenem single sodium salt

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Example 1: Preparation of Ertapenem Sodium

[0028] In a 250ml clean and dry three-neck flask, add 20.0g MAP (33.6mmol) and 14.5g (32.6mmol) monoprotected ertapenem side chain, add 150ml N,N-dimethylformamide, stir and dissolve under nitrogen protection, then cool down to -30°C, add 11g of diisopropylethylamine (85.1mmol) dropwise, after dropping, control the temperature at -20~-30°C for 14~16h, take a sample and test, the product purity is 97.34%; after the reaction is completed, add 150ml to the reaction solution Tetrahydrofuran, transfer the reaction solution into a hydrogenation kettle, add 150ml of 5% sodium bicarbonate aqueous solution, then add 3.0g of palladium carbon, put together the kettle, ventilate and test the pressure, pressurize to 0.8MPa, react at 25-30℃ for 2h, stop the reaction , filtered, the filtrate was washed with ethyl acetate, the lower aqueous phase was adjusted to pH = 5.0 with acetic acid, washed with n-butanol, the lower aqueous phase was ad...

Embodiment 2

[0030] Example 2: Preparation of Ertapenem Sodium

[0031] In a 250ml clean and dry three-neck flask, add 20.0g MAP (33.6mmol) and 16.48g (37.0mmol) mono-protected ertapenem side chain, add 80ml N,N-dimethylformamide, stir to dissolve under nitrogen protection, then cool down to -25°C, add 9.1g of diisopropylethylamine (70.4mmol) dropwise, and react at -8~-15°C for 2~4h after dropping, take a sample and test, the purity of the product is 96.85%; after the reaction is completed, add 300ml of ethyl acetate and tetrahydrofuran mixed solution, the reaction solution was transferred to a hydrogenation kettle, 300ml of 5% sodium bicarbonate aqueous solution was added, and then 4.0g of palladium carbon was added, the kettle was put together, the pressure was tested by ventilation, and the pressure was increased to 1.2MPa. React at 25°C for 4 hours, stop the reaction, filter, separate the filtrate, adjust the pH of the lower aqueous phase to 7.0 with acetic acid, wash with ethyl acetat...

Embodiment 3

[0032] Example 3: Preparation of Ertapenem Sodium

[0033]In a 250ml clean and dry three-neck flask, add 20.0g MAP (33.6mmol) and 15.0g (33.7mmol) monoprotected ertapenem side chain, add 150ml acetonitrile, stir and dissolve under nitrogen protection, cool to -35°C, add dropwise 8.5 g diisopropylamine (84.0mmol), react at -15~-25℃ for 12~14h after dropping, take a sample and test, the product purity is 97.32%; after the reaction is completed, add 300ml tetrahydrofuran to the reaction solution, and the reaction solution is transferred to hydrogenation In the kettle, add 150ml of 2% sodium bicarbonate aqueous solution, then add 5.0g of palladium carbon, close the kettle, ventilate and test the pressure, pressurize to 1.5MPa, react at 10~15℃ for 6h, stop the reaction, filter, add ethyl acetate to the filtrate Wash the lower aqueous phase with acetic acid to adjust pH=6.5, wash with ethyl acetate, adjust the lower aqueous phase to pH=6.0, add 0.6 times the volume of ethyl acetate ...

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Abstract

The invention discloses a preparation method of an ertapenem single sodium salt. The method comprises the following steps: dissolving a 1-beta-methyl carbapenem bicyclic parent nucleus and an ertapenem side chain in acetonitrile or DMF (N,N-dimethylformamide), and carrying out condensation in the existence of organic alkali until the reaction finishes; adding tetrahydrofuran or ethyl acetate or a tetrahydrofuran-ethyl acetate mixed solvent into the reaction solution, adding a sodium bicarbonate solution and palladium-carbon, and introducing hydrogen for hydrogenation; and after the reaction finishes, filtering, washing the filtrate, regulating different pH values of the water phase, washing, crystallizing by using a mixed solvent of two or three of alcohols, esters and ethers, filtering, and eluting the filter cake with acetone to obtain the ertapenem single sodium salt. The compounds disclosed as Formula 4 can be directly used for the next reaction step without separation, thereby avoiding the quality reduction of the compounds disclosed as Formula 4, and lowering the influence of the intermediate impurities on the subsequent technique. The solution can be directly crystallized, filtered, and dried to obtain the ertapenem sodium. The end product has the advantages of simpler purification, higher product quality and higher yield.

Description

technical field [0001] The invention belongs to the technical field of penem medicine synthesis, and in particular relates to a preparation method of ertapenem monosodium salt. Background technique [0002] Ertapenem sodium is a new type of spectrum carbapenem antibiotic jointly developed by Merck and AstraZeneca. The chemical name is (1R, 5S, 6S, 8R, 2S ＊ , 4S ＊ )-2-[2-[3-Carboxyl-phenylamino-formyl]-pyrrolidinyl-4-thio]-6-(1-hydroxyethyl)-1-methylcarbapenem-3 - Formic acid monosodium salt has good antibacterial activity against Gram-positive bacteria and negative aerobic bacteria and anaerobic bacteria. [0003] [0004] Patent CN104130262 lists various synthetic routes of ertapenem sodium. The main starting material is 1β-methyl carbapenem bicyclic nucleus (compound of formula 2) and double-protected ertapenem side chain (compound of formula a) or single-protected side chain of ertapenem (compound of formula b) or ertapenem Tapenem side chain hydrochloride (compoun...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D477/20C07D477/06
CPCC07D477/20C07D477/06
Inventor 周志成黄小庭孔令富尹涛熊毅张万通
Owner SHANGHAI LONGXIANG BIO MEDICINE DEV CO LTD
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