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Synthetic method for Tebipenem Pivoxil polymer impurity

A technology of tibipenem ester and synthesis method, which is applied in the field of preparation of polymer impurities, and can solve problems such as difficulty in purification, complex product components, and inability to be used in qualitative and quantitative research

Active Publication Date: 2014-04-09
上海津力药业股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The product of P8 obtained from the degradation of tibipenem ester is complex in composition, difficult to purify, and cannot be used for qualitative and quantitative research

Method used

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  • Synthetic method for Tebipenem Pivoxil polymer impurity
  • Synthetic method for Tebipenem Pivoxil polymer impurity
  • Synthetic method for Tebipenem Pivoxil polymer impurity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] The preparation of embodiment 1 T24

[0025] Add 200ml DMF, tibipenem (20g, 78.1mmol), triethylamine (17.34g, 156.2mmol), DMAP (0.3g, 2.6mmol), to the reaction flask in turn, cool down to 0°C, add TBSCl (45.2mmol) in batches g, 299.9 mmol). Complete the heat preservation at 0°C for 2 to 3 hours. Add EA / H to the reaction vial 2 O300ml / 300ml, liquid separation, the aqueous phase was extracted twice with ethyl acetate 300ml, the organic phase was combined, washed twice with saturated brine 300ml, the organic phase was dried with anhydrous magnesium sulfate, concentrated, purified by silica gel chromatography, and successively used Petroleum ether, ethyl acetate / petroleum ether (1 / 20), and ethyl acetate were eluted, and the eluate of the target compound was collected and concentrated to obtain the product (31.0g, 62.48mmol).

Embodiment 2

[0026] The preparation of embodiment 2 P10

[0027] Add 120ml DMF, P9 (20g, 49.8mmol), triethylamine (16ml, 115mmol), triethylbenzyl ammonium chloride (20g, 71.9mmol) to the reaction flask, heat up to 40-50°C, and add pivalic acid dropwise Chloromethyl ester (16ml, 106.6mmol), react for 1~2h. Add ethyl acetate / water 120ml / 120ml to the reaction bottle, separate the liquids, extract the aqueous phase with 120ml ethyl acetate, combine the organic phases, wash twice with saturated brine 120ml, dry the organic phases with anhydrous magnesium sulfate, and then concentrate. Purified by silica gel chromatography, eluted with ethyl acetate / petroleum ether (1 / 10), ethyl acetate / petroleum ether (1 / 5), ethyl acetate / petroleum ether (1 / 3) in sequence, and collected the fraction of the target compound The eluate was concentrated to give the product (25 g, 39.7 mmol).

Embodiment 3

[0028] The preparation of embodiment 3 T26

[0029] In a 250ml three-necked flask, add T24 (497mg, 1mmol), HOBt (152mg, 1mmol) and 50ml of DMF, cool down to -10°C, add DCC (206mg, 1mmol), stir for 30 minutes, add P10 (567mg, 0.9mmol) 10ml of DMF solution, complete the reaction at -10-0°C for 2-3 hours. Add 100ml of water / 100ml of ethyl acetate to the reaction solution for extraction, wash the organic phase with 50ml of water three times, dry the organic phase with anhydrous magnesium sulfate, and concentrate to dryness under reduced pressure. Use silica gel column chromatography, gradient elution with ethyl acetate / petroleum ether (1 / 20~1 / 1), collect the eluate of the target compound and concentrate to obtain T26 (942mg, 0.85mmol).

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Abstract

The invention provides a synthetic method for Tebipenem Pivoxil polymer impurity P8. The method employs a ring opening impurity P9 of Tebipenem and Tebipenem Pivoxil as a starting material, the starting material is subjected to an etherification reaction and an esterification reaction respectively, the obtained products are subjected to a condensation reaction and esters are formed; then t-butyl dimethyl silicon group protecting group is removed, after recrystallization purification, the target compound with a purity of being more than 90% is obtained. The target compound can be employed as a reference substance and used for qualitative and quantitative research of polymer impurities in Tebipenem Pivoxil quality research, thus contents of raw material Tebipenem Pivoxil related substances can be controlled, and quality of Tebipenem Pivoxil active pharmaceutical ingredients can be ensured.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, and further relates to a method for preparing polymer impurities of the carbapenem antibiotic tibipenem. Background technique [0002] Tybipenem pivoxate (I) is a new oral carbapenem drug developed by Wyeth Pharmaceuticals. The compound is a prodrug formed by the esterification of the C2 carboxylate of the active parent tibipenem. Tibipenem has a broad antibacterial spectrum. For most clinically isolated strains, Tibipenem has shown stronger antibacterial activity than penicillin series and cephalosporin series. Compared with other injectable carbapenem antibiotics, Tybipenem also showed the same degree or stronger antibacterial effect. Especially for PRSP (penicillin-resistant Streptococcus pneumoniae), MRSP (erythromycin-resistant Streptococcus pneumoniae) and Haemophilus influenzae (Haemophilus influenzae), which are the main causes of children's infections in recent years, have shown stro...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D477/20C07D477/06G01N30/02
CPCY02P20/55C07D477/20C07D477/06
Inventor 李瑞远刘立力张广明尹志媛柏江涛吕博雅袁庆
Owner 上海津力药业股份有限公司
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