- A versatile strategy for the solid-phase synthesis of penicillin derivatives: Efficient preparation of 2β-methyl substituted penams as β-lactamase inhibitor analogues
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A convenient solid-phase method for the synthesis of 2β-methyl substituted penicillins using commercially available resins is described. Functionalization of Merrifield and Wang resin bound penam derivatives was performed by penicillin sulfoxide rearrangement and the products were released from the supports under mild conditions. The utility of this methodology has been demonstrated by synthesizing a small library of penicillin derivatives in moderate to very good overall isolated yields for the multistep synthetic sequence. Georg Thieme Verlag Stuttgart.
- Boggian, Dora B.,Mata, Ernesto G.
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- β-Lactams on solid support: Mild and efficient removal of penicillin derivatives from Merrifield resin using aluminum chloride
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Penicillin derivatives linked to Merrifield resin are efficiently released from this support under mild conditions using aluminum chloride in dichloromethane/nitromethane. Extension to Wang resin-linked analogues and studies on the solid-phase oxidation of penicillin is also reported.
- Mata, Ernesto G.
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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; 0029; 0031; 0033; 0035; 0037
(2020/11/02)
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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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- 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; 0131
(2019/11/13)
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- Sulbactam sodium compound containing one-twentieth water and pharmaceutical composition thereof
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The invention discloses a sulbactam sodium compound containing one-twentieth water. The sulbactam sodium compound is white crystalline powder, and each mole of sulbactam sodium contains one-twentiethmole of water. The sulbactam sodium compound has main diffraction peaks at the positions with the corresponding main X-ray characteristic diffraction peak 2 theta angle of 14.23+/-0.2 degrees, 17.76+/-0.2 degrees, 19.22+/-0.2 degrees, 23.09+/-0.2 degrees, 24.60+/-0.2 degrees and 27.86+/-0.2 degrees. The sulbactam sodium compound prepared by means of a method has high stability and meets the requirements for being used a raw material of a preparation.
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Paragraph 0030; 0032; 0038; 0040; 0046; 0048
(2019/01/23)
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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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- 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 0041; 0045; 0047; 0049
(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 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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- 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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p. 377 - 387
(2007/10/03)
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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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- β-Lactamase inhibitors: Synthesis and in vitro evaluation of 6-[(1-substituted-1,2,3-triazol-4-yl)methylene]-penicillanic acid sulfones
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A series of 6-[(1-substituted 1,2,3-triazol-4-yl)methylene]penicillanic acid sulfones were synthesized and tested for β-lactamase inhibitory activity. The (6Z)-isomers were over 100 times more potent than the (6E)-isomers against cell-free β-lactamases an
- Eby, Paul,Cummings, Maxwell D.,Phillips, Oludotun A.,Czajkowski, David P.,Singh, Maya P.,Spevak, Paul,Micetich, Ronald G.,Maiti, Samarendra N.
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p. 653 - 668
(2007/10/03)
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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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- 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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- Preparation of 6,6-dibromo-penicillanic acid-1,1-dioxide
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In a process for the preparation of 6,6-dibromo-penicillanic acid-1,1-dioxide comprising reacting 6β-amino-penicillanic acid-1,1-dioxide with a nitrosating agent in the presence of bromine and an inorganic acid or strong organic acid, the improvement comprising effecting the reaction in the presence of an alcohol resulting in a high purity product.
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