- Synthesis and evaluation of novel β-lactam inhibitors of human leukocyte elastase
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A series of β-lactam derivatives were synthesized and tested to determine the structure-activity relationship for inhibition of human leukocyte elastase (HLE), a serine protease involved in several degenerative lung and tissue diseases. The most potent IC50 values were obtained with neutral hydrophobic 7α-methoxy cephalosporanic acid derivatives. Tryptophanyl-9-fluorenylmethyl ester and N-benzhydryl piperazine derivatives of 7α-methoxy cephalosporanic acid represent two novel HLE inhibitors, with length of action persisting beyond 24 h.
- Koteva,Cantin,Neugebauer,Escher
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- Synthesis and antibacterial evaluation of sulbactam derivatives against Acinetobacter baumannii
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Sulbactam, a known β-lactamase inhibitor, was found to own potent antimicrobial activity against Acinetobacter baumannii in clinical practice. Based on clinical evidence, a series of sulbactam derivatives were designed, synthesized and evaluated for antibacterial activity against Acinetobacter baumannii, taking sulbactam as the lead. Among them, compound 9 exhibited a good antibacterial activity against Acinetobacter baumannii with a MIC value of 4 μg/mL, slightly lower than that of sulbactam of 1 μg/mL. Especially, compound 9 displayed outstanding oral pharmacokinetic profiles with a maximum plasma concentration (Cmax) of 19.6 μg/mL and area under the curve (AUC) of 10.8 μg?h/mL, much higher than those of sulbactam, and thus held the potential of being developed into an oral medication. These results provided the useful information for further structural modification and optimization of its kind, and compound 9 has been selected for the further investigation.
- Yang, Yuanshuai,Tang, Sheng,Liu, Zhandong,Wang, Yanxiang,Pang, Jing,You, Xuefu,Song, Danqing,Li, Yinghong,Lu, Xi
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- Synthesis method of sulbactam
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The invention relates to a synthesis method of sulbactam, and belongs to the field of beta-lactamase inhibitor synthesis. In the method, 6-aminopenicillanic acid (6-APA) as a raw material is dissolvedin an organic solvent, and is adopted together with bromine as substrates under a strong acid condition, 6,6-dibromo penicillanic acid is formed through diazotization bromination in a manner of dropwise adding a sodium nitrite solution, and then one-step oxidation and reduction are performed to obtain sulbactam. According to the method, a hydrogen peroxide one-step oxidation mode is adopted, andthe use of potassium permanganate is avoided from the source, so that the generation of waste salt is reduced, and meanwhile, the use of a large amount of ethyl acetate is avoided. The method not onlyreduces the emission of three wastes from the source and greatly reduces the emission of organic matters and waste salt in the original process, but also greatly reduces the side reaction and the rawmaterial cost.
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Paragraph 0027-0028; 0031-0032; 0035-0036
(2020/11/02)
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- New indications of troxofine ceftriaxone sodium pharmaceutical preparation for treatment of infection of patients with immunodeficiency
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The invention belongs to the technical field of drug preparation, and discloses new indications of a troxofine ceftriaxone sodium pharmaceutical preparation for treatment of infection of patients withimmunodeficiency. By improving a raw material synthesis process, ceftriaxone sodium with the high effective constituent content and the low impurity content is provided so as to solve the problems ofpoor stability and reducing of the antibacterial effect of a ceftriaxone sodium preparation due to impurities. The ceftriaxone sodium provided by the specific production process is very low in impurity content and significant in efficacy, the quality of a preparation product is improved advantageously, safety and effectiveness of the preparation product are ensured, and the preparation product has uses in the aspects of preparing drugs for treating infection of the patients with immunodeficiency.
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Paragraph 0129; 0130
(2019/11/13)
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- C type beta-lactamase inhibitor, and preparation method and applications thereof
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The invention provides a C type beta-lactamase inhibitor. The C type beta-lactamase inhibitor is 6 alpha-(1R-hydroxy-3(2-thiophene-yl)propyl) penicillic acid, and the structure of the C type beta-lactamase inhibitor is represented by formula 1 in the invention.
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Paragraph 0055; 0059; 0064; 0065
(2019/03/28)
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- Extends the batanbatan acid synthesis method (by machine translation)
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The present invention relates to the field of drug synthesis, directed to the problem of low yield synthesis mode, provides a method of synthesizing extends the batanbatan acid, comprises the following steps: S1, diazotization and bromination reaction: in the 6 - amino penicillanic acid bromine is added in, the dilute sulfuric acid solution and sodium nitrite solid, dilute sulfuric acid concentration of the solution is 20% - 25%, to obtain the 1st intermediate; S2, oxidation reaction: to the 1st intermediate dropping potassium permanganate and dilute sulfuric acid solution, the concentration of the dilute sulfuric acid solution is 20% - 25%; S3, hydrogenation reaction: to the 2nd intermediate [...] and in dilute sulfuric acid solution, to obtain the extends the batanbatan acid. By using the 20% - 25% of the dilute sulfuric acid solution react, help to improve the diazo and bromination reaction and oxidation reaction of the active, so that the reactant more completely, thus help to improve the diazo and bromination reaction and oxidation of the yield of the reaction, and then make the overall yield of the reaction. (by machine translation)
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Page/Page column 5-15
(2019/03/31)
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- Method for preparing sulbactam acid
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The invention relates to the field of pharmaceutical synthesis and provides a method for preparing sulbactam acid. The method is used for solving the problem of the traditional synthesis methods thatthe yield is low. The method comprises the following steps: S1. diazotation and bromination reaction: adding bromine, a dilute sulfuric acid solution and sodium nitrite solids into 6-aminopenicillanicacid, so as to obtain a first intermediate, wherein the dilute sulfuric acid solution adopts depleted deuterium water as a solvent; S2. oxidation reaction: dropwise adding potassium permanganate anda dilute sulfuric acid solution into the first intermediate, so as to obtain a second intermediate; and S3. hydrogenation reaction: add strontium powder and a dilute sulfuric acid solution into the second intermediate, thereby obtaining a product, i.e., the sulbactam acid, wherein the dilute sulfuric acid solution adopts depleted deuterium water as a solvent. Through preparing the dilute sulfuricacid solution by adopting the depleted deuterium water as the solvent and adopting the strontium powder as a catalyst, the improvement on reaction activity of dilute sulfuric acid is facilitated, theconversion ratio of reaction is increased, and thus, the increase of reaction yield is facilitated, so that the yield of reaction can be higher than 90%.
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Page/Page column 5-11
(2019/05/15)
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- A 6, 6 - DEHALOGEHATION of 6.6 preparation method
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The invention discloses a 6, 6-dibromo penicillanic acid preparation method which is as follows: at the temperature of-20 to 0 DEG C, sodium nitrite is slowly added into a hydrobromic acid solution dissolved with bromide to produce and separate a black active solution containing nitrosyl bromide, bromide and sodium bromide; then the solution is dripped into a 6-APA hydrobromic acid solution of the temperature of-25 to 5 DEG C; after the completion of reaction, reaction liquid is filtered, and the product 6, 6-dibromo penicillanic acid is obtained by washing and vacuum drying of the filter cake. The method completely does not use an organic solvent, is simple in post-processing, improves the utilization rate of the bromide and the hydrobromic acid, ensures the safety of production and reduces the cost, and the product yield of 96.5% or higher.
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Paragraph 0005; 0006; 0031-0045
(2017/08/25)
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- New synthesis method for sulbactam acid
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The invention discloses a new synthesis method for sulbactam acid. The new synthesis method comprises the following steps: performing reaction between 6-amino-penicillanic acid and sodium nitrite and bromine in water-insoluble organic solvent under an acidic condition to obtain a reaction product: bis-bromo-penicillanic acid, and then, performing oxidation reaction and hydrogenation to obtain sulbactam. According to the new synthesis method disclosed by the invention, by adopting the water-insoluble solvent, emission of organic matter in water is reduced; by adopting a mode of step-by-step-oxidation, not only is the usage level of potassium permanganate reduced but also the phenomenon that a large amount of ethyl acetate is used originally is avoided; filtering separation is performed on manganese dioxide by the solvent, and thus, not only is emission of the three wastes reduced but also the solvent can also be utilized as a by-product; emission of organic matter and waste salt in an original process is greatly reduced, and side reaction and raw material cost are also greatly reduced.
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Paragraph 0030; 0034; 0038; 0042; 0046; 0050; 0054; 0058
(2017/08/23)
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- A [...] synthetic method
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The invention discloses a synthetic method of salbactam acid. The synthetic method comprises the following steps: carrying out diazotized bromination reaction on 6-aminopenicillanic acid to form bromopenicillanic acid; and then, carrying out oxidation reaction and reduction reaction to obtain salbactam acid, wherein in the diazotized bromination reaction, 6-aminopenicillanic acid is continuously added in form of an acidic solution, the acidic solution of 6-aminopenicillanic acid is 5-8% sulfuric acid aqueous solution, 13-15% hydrobromic acid aqueous solution or 5-8% hydrochloric acid aqueous solution. 6-aminopenicillanic acid is dropwise added in form of the acidic solution, so that dust pollution is avoided and the work environment of field personnel is improved. Meanwhile, 6-aminopenicillanic acid exists in form of stable salt, decomposition reaction is avoided, and the reaction quality is improved. The three-step yield of the method is over 70%, the HPCL purity is over 99.7%, the individual impurity content is less than 0.1% and the total impurity content is less than 0.5%.
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Paragraph 0040; 0044; 0047; 0048; 0051-0058; 0061; 0062
(2017/08/25)
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- Synthesis and crystal of methyl 6,6-dihydropenicillanate S,S-dioxide
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6,6-dihydropenicillanate S,S-dioxide 5 was prepared and determined by X-ray crystallography. Single-crystal X-ray diffraction analysis reveals that the molecular structure of compound 5b is enantiomerically pure. The crystal belongs to orthorhombic, space group P212121, with unit cell parameters a = 6.5366 A, b = 10.7649(9) A, c = 15.5879(13) A, V = 1096.86(16) A3, Dx = 1.491 g cm 3, Z = 4, T = 296(2)K, F(000) = 520, R 1 = 0.0401, and wR 2 = 0.1200. Absolute structure parameter is 0.02(10).
- Zhang, H.-L.,Zhang, Y.-M.,Liu, P.,Wang, Y.-Q.
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p. 1083 - 1086,4
(2020/08/31)
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- Synthesis and biological evaluation of penem inhibitors of bacterial signal peptidase
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We report the first synthesis of a 5S penem, known to bind bacterial type I signal peptidase, from the commercially available and inexpensive 6-aminopenicillanic acid. We report the first in vivo activity of the compound and use structure-activity relationship studies to begin to define the determinants of signal peptidase binding and also to begin to optimize the penem as an antibiotic.
- Harris, David A.,Powers, Michael E.,Romesberg, Floyd E.
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scheme or table
p. 3787 - 3790
(2010/03/25)
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- Rational design of a β-lactamase inhibitor achieved via stabilization of the trans-enamine intermediate: 1.28 A crystal structure of wt SHV-1 complex with a penam sulfone
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β-Lactamases are one of the major causes of antibiotic resistance in Gram negative bacteria. The continuing evolution of β-lactamases that are capable of hydrolyzing our most potent β-lactams presents a vexing clinical problem, in particular since a number of them are resistant to inhibitors. The efficient inhibition of these enzymes is therefore of great clinical importance. Building upon our previous structural studies that examined tazobactam trapped as a trans-enamine intermediate in a deacylation deficient SHV variant, we designed a novel penam sulfone derivative that forms a more stable trans-enamine intermediate. We report here the 1.28 A resolution crystal structure of wt SHV-1 in complex with a rationally designed penam sulfone, SA2-13. The compound is covalently bound to the active site of wt SHV-1 similar to tazobactam yet forms an additional salt-bridge with K234 and hydrogen bonds with S130 and T235 to stabilize the frans-enamine intermediate. Kinetic measurements show that SA2-13, once reacted with SHV-1 β-lactamase, is about 10-fold slower at being released from the enzyme compared to tazobactam. Stabilizing the trans-enamine intermediate represents a novel strategy for the rational design of mechanism-based class A β-lactamase inhibitors.
- Padayatti, Pius S.,Sheri, Anjaneyulu,Totir, Monica A.,Helfand, Marion S.,Carey, Marianne P.,Anderson, Vernon E.,Carey, Paul R.,Bethel, Christopher R.,Bonomo, Robert A.,Buynak, John D.,Van Den Akker, Focco
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p. 13235 - 13242
(2008/03/11)
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- Synthesis and evaluation of 3-(carboxymethylidene)- and 3-(carboxymethyl)penicillinates as inhibitors of β-lactamase
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Penicillin-resistant bacteria can often be treated through the co-administration of an antibiotic and a β-lactamase inhibitor. Current inhibitors target only class Aβ-lactamases. We report two new series of C3-modified penicillin sulfones, having either a simple methylene group (i.e., a homologue) or exocyclic unsaturation between the thiazolidine ring and the C3 carboxylate. The homologue has 10-fold better activity against a class C β-lactamase than does sulbactam itself. By contrast, the exocyclic C3 unsaturated compounds are less active.
- Buynak, John D.,Ghadachanda, Venkat Rao,Vogeti, Lakshminaryana,Zhang, Hongming,Chen, Hansong
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p. 4510 - 4513
(2007/10/03)
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- Penicillin-derived inhibitors that simultaneously target both metallo- and serine-β-lactamases
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The synthesis and β-lactamase inhibitory activity of four 6-(mercaptomethyl)penicillinates and the four corresponding 6-(hydroxymethyl) penicillinates are described. These penicillins include both C6 stereoisomers as well as the sulfide and sulfone oxidation states of the penam thiazolidine sulfur. All compounds were evaluated as inhibitors of representative metallo- and serine-β-lactamases enzymes. Selected (mercaptomethyl)penicillinates are shown to inactivate both metallo- and serine-β-lactamases and to display synergism with piperacillin against β-lactamase producing strains.
- Buynak, John D.,Chen, Hansong,Vogeti, Lakshminaryana,Gadhachanda, Venkat Rao,Buchanan, Christine A.,Palzkill, Timothy,Shaw, Robert W.,Spencer, James,Walsh, Timothy R.
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p. 1299 - 1304
(2007/10/03)
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- Inhibitors of serine and metallo-beta-lactamases
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Compounds of formula (I): 1wherein R1, R2, R3, R4 and n have any of the values defined in the specification, and their pharmaceutically acceptable salts, are useful for inhibiting simultaneously serine and metallo-β-lactamase enzymes, for enhancing the activity of β-lactam antibiotics, and for treating β-lactam resistant bacterial infections in a mammal. The invention also provides pharmaceutical compositions, processes for preparing compounds of formula I, and novel intermediates useful for the synthesis of compounds of formula I.
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- Process for producing halogenated β-lactam compound
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A process for preparing halogenated β-lactam compounds, characterized in that a β-lactam amino compound of the formula (1) is reacted with nitrous acid or nitrite in a slurry dispersion state in water, under acid condition in the presence of halogen molecules, thereby obtaining a halogenated β-lactam compound of the formula (4) wherein n is an integer of 0 to 2; A is the formula (2) or (3); R1and R2are the same or different and are hydrogen atom, halogen atom, C1?C3alkyl group, C2?C4alkenyl group, C2?C4alkynyl group, nucleophilic group, or CH2R3; and R3is halogen atom or nucleophilic group ?wherein A is as defined above; X1is hydrogen atom or halogen atom; and X2is halogen atom.
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- Dipolar cycloaddition of novel 6-(nitrileoxidomethyl) penam sulfone: an efficient route to a new class of beta-lactamase inhibitors.
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6-(Nitrileoxidomethyl) penam sulfone intermediate was prepared in a few steps starting from commercially available (+)-6-aminopenicillanic acid. This intermediate underwent smooth 1, 3-dipolar cycloaddition reactions with various alkenes and alkynes to give cycloadducts in moderate to good yields. By this new method, several potent beta-lactamase inhibitors were synthesized. The regio- and stereoselectivity outcomes of the cycloaddition process are also discussed.
- Sandanayaka,Yang
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p. 3087 - 3090
(2007/10/03)
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- Scope and Mechanism of Deprotection of Carboxylic Esters by Bis(tributyltin) Oxide
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Methyl and ethyl esters of aliphatic and aromatic carboxylic acids as well as benzyl carboxylates, thiol esters and double esters such as (pivaloyloxy)methyl carboxylates have been successfully cleaved with bis(tributyltin) oxide to give the free carboxylic acids in good yields.The reaction is carried out in aprotic solvents under essentially neutral conditions and thus this method can serve as an ideal procedure for the cleavages of esters with other functional groups and/or protecting groups acid and/or base sensitive.We demonstrated that the reaction displays a high level of chemoselectivity between methyl and ethyl esters versus tert-butyl esters and γ-lactones.Bis(tributyltin) oxide is also a highly efficient reagent for the cleavage of acetates of primary and secondary alcohols and phenols.The limitations we found in the use of this reagent include the lack of cleavage of esters sterically hindered around the carboxyl carbon and the carbinol group (i.e., esters of tertiary alcohols) and in carboxylic esters that contain a fluoroalkyl substituent.A resonable mechanistic explanation is discussed to account for the reaction pathway of the acyloxygen cleavage of (-)-(1R)-menthyl acetate.
- Salomon, Claudio J.,Mata, Ernesto G.,Mascaretti, Oreste A.
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p. 7259 - 7266
(2007/10/02)
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- SOME APPROACHES TO THE SYNTHESIS OF SULBACTAM
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A study on the synthesis of penicillanic acid 1,1-dioxide, Sulbactam, was carried out.Two reliable convergent synthetic routes to this β-lactamase inhibitor starting from penicillin G potassium salt and 6-aminopenicillanic acid have been developed.
- Husinec, Suren,Dragovic, Deana,Stokic, Zdenka,Kojic, Josipa
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p. 1370 - 1375
(2007/10/02)
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- Improved method for preparing penicillanic acid derivatives
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The present invention relates to a new process for the debromination and/or deiodination of 6,6-dihalo- and 6-monohalopenicillanic acids or derivatives thereof by treatment with dialkyl, trialkyl or diaralkyl phosphite, the desired compounds being obtained in good to excellent yield and in a high state of purity.
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- 6,6-dihalopenicillanic acid 1,1-dioxides and process
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A process for the preparation of penicillanic acid 1,1-dioxide and esters thereof readily hydrolyzable in vivo, which comprises oxidation of a 6,6-dihalopenicillanic acid, or an ester thereof readily hydrolyzable in vivo, to the corresponding 6,6-dihalopenicillanic acid 1,1-dioxide or ester thereof, followed by dehalogenation (e.g. by hydrogenolysis). The 6,6-dihalopenicillanic acid 1,1-dioxides and esters thereof readily hydrolyzable in vivo are novel intermediates. Penicillanic acid 1,1-dioxide, and esters thereof readily hydrolyzable in vivo, are known compounds which are useful as beta-lactamase inhibitors and for enhancing the effectiveness of certain beta-lactam antibiotics (e.g. the penicillins) in the treatment of bacterial infections in mammals, particularly humans.
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- SYNTHESIS OF OPTICALLY ACTIVE PENEMS
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A general synthesis for optically active penems is described.Penems undergo a novel thermal isomerisation reaction.
- Girijavallabhan, V. M.,Ganguly, A. K.,McCombie, S. W.,Pinto, P.,Rizvi, R.
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p. 3485 - 3488
(2007/10/02)
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- Penicillanic acid 1,1-dioxides as β-lactamase inhibitors
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Penicillanic acid 1,1-dioxide, and esters thereof readily hydrolyzable in vivo, are useful as antibacterial agents, and also for enhancing the effectiveness of several β-lactam antibiotics against many β-lactamase producing bacteria. Derivatives of penicillanic acid 1,1-dioxide having the carboxy group protected by a conventional penicillin carboxy protecting group are useful intermediates to penicillanic acid 1,1-dioxide. Penicillanic acid 1-oxides and certain esters thereof are useful chemical intermediates to penicillanic acid 1,1-dioxide and its esters.
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