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Optically-active diazabicyclooctane derivative and method for manufacturing same

A diazacyclic, optically active technology, applied in the field of optically active diazacyclooctane derivatives, can solve the problem of fewer candidates for development

Active Publication Date: 2013-09-25
MEIJI SEIKA KAISHA LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, more than 250 β-lactamases have been reported so far, among which, in addition to the proliferation of C-type β-lactamases and extended-spectrum β-lactamases (ESBLs) belonging to A and D types, the type, and even KPC-2 resistant bacteria that break down carbapenems, the last bastion of β-lactam antibacterials, are also seen as problems
For these β-lactamases, the above-mentioned commercially available inhibitors are ineffective. Therefore, there is a strong demand for the development of new inhibitors. However, there are only reports of potential inhibitors, and there are few candidates for further development.

Method used

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  • Optically-active diazabicyclooctane derivative and method for manufacturing same
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  • Optically-active diazabicyclooctane derivative and method for manufacturing same

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preparation example Construction

[0121] Among the compounds represented by the formula (F) of the present invention obtained by the above-mentioned production method of the present invention, the following formulas (F1), (F1-3a), (F1-3b), (F1-1a), (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazacyclo[3.2.1]octane-2- represented by (F1-2) and (F1-4) tert-butyl carboxylate, (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazacyclo[3.2.1]octane-2-carboxylate methyl ester, (2S,5R)-6-(Benzyloxy)-7-oxo-1,6-diazacyclo[3.2.1]octane-2-carboxylic acid allyl ester, (2S,5R)- Cyclohexylammonium salt of 6-(benzyloxy)-7-oxo-1,6-diazacyclo[3.2.1]octane-2-carboxylic acid, (2S,5R)-6-(benzyloxy base)-7-oxo-1,6-diazacyclo[3.2.1]octane-2-carboxylic acid and (2S,5R)-6-(benzyloxy)-7-oxo-1, 6-diazacyclo[3.2.1]octane-2-carboxamide can be obtained in the form of crystals of optically active diazacyclooctane derivatives, so it has the advantages of easy separation, purification, storage and transportation . This shows that the present invention is an indust...

Embodiment 1

[0413] (2S,5S)-5-Hydroxypiperidine-2-carboxylic acid tert-butyl ester (B)

[0414] [chemical formula 46]

[0415]

[0416] Add 10% palladium carbon ( moisture about 50%) 10.1 g, stirred vigorously at room temperature overnight under a hydrogen atmosphere. The catalyst mixture was filtered through celite, and the filtrate was concentrated to obtain 39.3 g of the title compound as a colorless solid (97% yield). The excess rate of optically active substances is above 99%ee (CHIRALPAK AD-H, 4.6×150mm, UV210nm, diethylamine / hexane / ethanol=0.1 / 80 / 20, flow rate 1mL / min, retention time 6.3min).

[0417] [α] 20 D -28.7°(c1.01, CHCl 3 ); 1 H NMR (400MHz, CDCl 3 ,δ):1.47(s,9H),1.63(m,1H),1.79-1.84(m,3H),2.82(dd,J=12.2,2.2Hz,1H),3.02(ddd,J=12.2,3.7 ,1.7Hz,1H),3.21(m,1H),3.80(m,1H);MS m / z:202(M+1).

Embodiment 2

[0419](2S,5S)-5-Hydroxy-1-(2,2,2-trifluoroacetyl)piperidine-2-carboxylic acid tert-butyl ester (C)

[0420] [chemical formula 47]

[0421]

[0422] Under argon atmosphere, the solution of 39.14 g (194 mmol) of (2S,5S)-5-hydroxypiperidine-2-carboxylic acid tert-butyl ester in anhydrous tetrahydrofuran (450 mL) was cooled to -3~-5 °C, and three 78.7 g (776 mmol) of ethylamine, and 81.5 g (388 mmol) of trifluoroacetic anhydride were added dropwise over 30 minutes. The reaction mixture was reacted at -3~-5°C for 1 hour, water (90 mL) was added, the temperature was raised to room temperature, and stirred for 1 hour. Water (740mL) was added to the reaction mixture, extracted with ethyl acetate (450mL×3 times), and the combined organic layer was sequentially washed with 5% aqueous citric acid (450mL), 6.5% aqueous sodium bicarbonate (450mL) and water ( 450mL) for washing. The residue obtained by distilling off the solvent under reduced pressure was subjected to silica gel colum...

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Abstract

Provided are an optically-active diazabicyclooctane derivative represented by a formula (F) that is useful as a medicinal intermediate of a ss-lactamase inhibitor, and a method for manufacturing the same. In the formula (F), R1 represents CO2R, CO2M, or CONH2; R represents a methyl group, a tert-butyl group, an allyl group, a benzyl group, or a 2,5-dioxopyrrolidine-1-yl group; M represents a hydrogen atom, an inorganic cation, or an organic cation; and R2 represents a benzyl group or an allyl group.

Description

technical field [0001] The present invention relates to an optically active diazacycloctane derivative represented by the following formula (F) useful as a pharmaceutical intermediate of a β-lactamase inhibitor and a method for producing the same. [0002] [chemical formula 1] [0003] [0004] In the above formula (F), R 1 means CO 2 R, CO 2 M or CONH 2 , R represents methyl, tert-butyl, allyl, benzyl or 2,5-dioxopyrrolidin-1-yl, M represents a hydrogen atom, an inorganic cation or an organic cation, R 2 Represents benzyl or allyl. Background technique [0005] Penicillins and cephalosporins are the most widely and frequently used β-lactam antibiotics in the medical field. However, in various infectious pathogenic bacteria, resistance to β-lactam antibacterial drugs reduces the therapeutic effect on bacterial infectious diseases. The most prominent resistance mechanism is the production of β-lactamases of type A, C and D with serine residues in the active center. ...

Claims

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Application Information

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IPC IPC(8): C07D471/08A61K31/439A61P31/04A61P43/00C07D211/60
CPCC07D211/60C07D471/08A61K31/431A61P31/00A61P31/04A61P43/00A61K2300/00A61K31/439
Inventor 阿部隆夫奥江雅之坂卷仪晃
Owner MEIJI SEIKA KAISHA LTD
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