- METHOD FOR PRODUCING AMINO ACID DERIVATIVES
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The present invention aims to provide a method for producing a (2S,5R)-5-(protected oxyamino)-piperidine-2-carboxylic acid derivative at a low cost that can be performed under mild reaction conditions not requiring a facility at an extremely low temperature, is safer, can control the quality of the desired product with ease, and shows good workability in the site of production. A method for producing a compound represented by the formula (2): wherein PG1 is an amino-protecting group, PG2 is an amino-protecting group, PG3 is a hydroxyl-protecting group, LG is a leaving group, and R is a hydrocarbon group having 1-8 carbon atoms and optionally having substituent(s), including a step of reacting a compound represented by the formula (1): wherein each symbol is as defined above, with a hydroxylamine derivative represented by the formula PG2NHOPG3 wherein each symbol is as defined above, in the presence of a base in a solvent.
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- Method of preparing 5R-[(benzyloxy) amino] piperidine-2S-carboxylic acid or a derivative thereof
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The present application relates to methods of preparing 5R-[(benzyloxy) amino] piperidine-2S-carboxylic acid or its derivatives in an environment-friendly way. The method uses L-glutamic acid as a starting material, which is first subjected to esterification reaction in the presence of an acidic reagent, and then reacted successively with 2-haloacetate and N-protecting agent, or with N-protecting agent and 2-haloacetate under a basic condition to obtain compound IV; then, the obtained compound IV is subjected to intramolecular condensation into a ring under the action of a strong base to obtain N-protecting group piperidine-5-one-2S-carboxylate (V).
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- NEW BETA-LACTAMASE INHIBITORS TARGETING GRAM NEGATIVE BACTERIA
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The present invention relates to a compound of the following formula (I) or a pharmaceutically acceptable salt and/or solvate thereof, notably for use as β-lactamase inhibitors, notably in the treatment of a disease caused by gram negative bacteria, in particular enterobacteria, as well as pharmaceutical compositions containing such a compound and a process to prepare such a compound.
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- NEW ANTIBIOTICS TARGETING MYCOBACTERIA
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The present invention relates to a compound of the following formula (I) or a pharmaceutically acceptable salt and/or solvate thereof, notably for use as a drug, notably in the treatment of a disease caused by mycobacteria, as well as pharmaceutical compositions containing such a compound and a process to prepare such a compound.
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- Synthesis of Avibactam Derivatives and Activity on β-Lactamases and Peptidoglycan Biosynthesis Enzymes of Mycobacteria
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There is a renewed interest for β-lactams for treating infections due to Mycobacterium tuberculosis and M. abscessus because their β-lactamases are inhibited by classical (clavulanate) or new generation (avibactam) inhibitors, respectively. Here, access to an azido derivative of the diazabicyclooctane (DBO) scaffold of avibactam for functionalization by the Huisgen–Sharpless cycloaddition reaction is reported. The amoxicillin–DBO combinations were active, indicating that the triazole ring is compatible with drug penetration (minimal inhibitory concentration of 16 μg mL?1 for both species). Mechanistically, β-lactamase inhibition was not sufficient to account for the potentiation of amoxicillin by DBOs. Thus, the latter compounds were investigated as inhibitors of l,d-transpeptidases (Ldts), which are the main peptidoglycan polymerases in mycobacteria. The DBOs acted as slow-binding inhibitors of Ldts by S-carbamoylation indicating that optimization of DBOs for Ldt inhibition is an attractive strategy to obtain drugs selectively active on mycobacteria.
- Edoo, Zainab,Iannazzo, Laura,Compain, Fabrice,Li de la Sierra Gallay, Inès,van Tilbeurgh, Herman,Fonvielle, Matthieu,Bouchet, Flavie,Le Run, Eva,Mainardi, Jean-Luc,Arthur, Michel,Ethève-Quelquejeu, Mélanie,Hugonnet, Jean-Emmanuel
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p. 8081 - 8086
(2018/05/30)
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- Convenient preparing methods for 5R-benzyloxyaminopiperidine-2S-formate and oxalate thereof
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The invention relates to convenient preparing methods for 5R-benzyloxyaminopiperidine-2S-formate and oxalate thereof. L-glutamic acid is adopted as an initial raw material and esterified under the existence of an acidic agent to prepare a compound III; the compound III and 2-halogen-acetate are reacted under an alkaline condition to obtain a compound IV; the compound IV is subjected to intramolecular condensation and cyclization under functions of a strong alkali to obtain piperidin-5-one-2S-formate; the piperidin-5-one-2S-formate and benzylhydroxylamine hydrochloride are subjected to a condensation reaction under the existence of an alkali to obtain 5-benzyloxy imino piperidine-2S-formate; the 5-benzyloxy imino piperidine-2S-formate is subjected to reduction and chiral resolution to obtain the 5R-benzyloxyaminopiperidine-2S-formate oxalate; and the 5R-benzyloxyaminopiperidine-2S-formate oxalate is neutralized to obtain the 5R-benzyloxyaminopiperidine-2S-formate. The invention also provides a method for preparing avibactam. Raw materials of the methods are easily available, the methods are simple to operate, a production process is environmentally friendly, yields are high, and a production cost of the avibactam can be reduced.
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- A method of recovering and utilizing avibactam intermediate production waste liquid
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The invention relates to a method of recovering and utilizing avibactam intermediate production waste liquid. The waste liquid produced in a production process of an avibactam intermediate that is 5R-benzyloxyaminopiperidine-2S-formateoxalate IIb is adopted as an initial raw material, and is oxidized to generate 5R-benzyloxyiminopiperidine-2S-formate III; the compound III is subjected to selectivereduction, chiral crystallization resolution and filtration to obtain the solid 5R-benzyloxyaminopiperidine-2S-formateoxalateoxalate IIb; and the obtained filtrate is subjected to the oxidation, reduction and resolution steps again. The compound IIb is neutralized to prepare 5R-benzyloxyaminopiperidine-2S-formate IIa, and the compound IIa or the compound IIb can be utilized to prepare avibactam I. The method is simple and convenient to operate, the atom utilization rate is increased, and the total yield of the compound IIb can be 99.0% or above, thus facilitating cost reduction, facilitatingreduction of avibactam waste liquid and facilitating environment protection.
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Paragraph 0064; 0065
(2018/03/01)
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- Production method for diazabicyclooctane derivative and intermediary body thereof
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The present invention provides a production method for a diazabicyclooctane derivative expressed by formula (IV), and an intermediary body thereof (in the formula: P is an acid-removable NH protective group; R1 represents a 2, 5-dioxopyrrolidine-1-yl, a 1, 3-dioxo-3a, a 4, 7, 7a-tetrahydro-1H-isoindole-2(3H)-yl, a 1, 3-dioxohexahydro-1H-isoindole-2(3H)-yl, or a 3, 5-dioxo-4-azatricyclo[5.2.1.02, 6]deca-8-en-4-yl; R2 represents hydrogen, C1CO-, or C13COCO-, R3 represents a C1-6 alkyl or a heterocyclyl, or joins with a bonded -O-NH- to form a 3-7 member heterocyclyl ring; and OBn represents a benzyloxy).
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- CRYSTALLINE FORMS OF DIAZABICYCLOOCTANE DERIVATIVE AND PRODUCTION PROCESS THEREOF
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A crystalline form of a diazabicyclooctane derivative represented by the following Formula (VII), and processes for producing the same:
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Paragraph 0198; 0199
(2016/10/11)
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- CRYSTAL OF DIAZABICYCLEOCTANE DERIVATE AND METHOD FOR PRODUCING THE SAME
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The present invention provides a crystal of diazabicycleoctane derivate represented by the following formula (VII), especially formula (VII-1), and a method for producing the same.
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Paragraph 0123
(2017/02/02)
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- NOVEL -LACTAMASE INHIBITOR AND METHOD FOR PRODUCING SAME
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The currently available β-lactamase inhibitors are insufficient to inhibit the incessantly increasing β-lactamase, and novel β-lactamase inhibitors has been required today for the difficult treatment for bacterial infectious diseases caused by resistant bacteria which produce class C β-lactamase, extended-spectrum β-lactamase (ESBL) belonging to class A and D, or class A KPC-2 decomposing even carbapenem as a last resort for β-lactam antibiotic. A compound represented by the the formula (I), preparation process of the same, β-lactamase inhibitors and method for treating bacterial infectious diseases are provided.
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