- A combined experimental-computational study of benzoxaborole crystal structures
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Benzoxaboroles are organoboron molecules which are gaining growing interest in different fields, notably for the development of new drugs. However, extensive characterization of these molecules in the solid state is still lacking. Here, questions related to the structure and spectroscopic signatures of crystalline benzoxaborole phases are thus addressed, using a combined experimental-computational approach. Two simple benzoxaboroles were studied: 1,3-dihydro-1-hydroxy-2,1-benzoxaborole (denoted as BBzx) and 5-fluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (also referred to as AN2690, a newly developed antifungal drug). First, the crystal structures of AN2690 and BBzx at room temperature are discussed, emphasizing the intermolecular interactions which play an important role in their formation. Then, results of IR and multinuclear (1H, 11B, 13C and 19F) solid state NMR characterization are presented, together with density functional theory (DFT) calculations which were carried out to assist in the interpretation of the spectra. Finally, the influence of polymorphism and anisotropic thermal expansion properties of the crystal structures on the NMR parameters of BBzx and AN2690 is discussed.
- Sene, Saad,Berthomieu, Dorothee,Donnadieu, Bruno,Richeter, Sebastien,Vezzani, Joris,Granier, Dominique,Begu, Sylvie,Mutin, Hubert,Gervais, Christel,Laurencin, Danielle
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- Transition-metal-free, one-pot synthesis of benzoxaboroles from: O -bromobenzaldehydes via visible-light-promoted borylation
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A novel and simple one-pot stepwise method to synthesize benzoxaboroles was demonstrated. This step-by-step synthetic method includes photocatalytic boronization with phenothiazine as a photocatalyst and sequential water-induced reduction in the presence of bis(pinacolato)diboron. A series of o-bromobenzaldehydes were well-tolerated under the standard conditions. In addition, this method has been successfully applied in the synthesis of the anti-tuberculosis candidate drug GSK 3036656 and anti-fungal drug tavaborole. This journal is
- Chen, Jianchao,Hu, Yanjun,Jia, Xingxing,Luo, Jinghan,Sun, Tiemin
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p. 10455 - 10459
(2021/12/17)
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- Benzoxaborole-1-alcohol compound and preparation method and application thereof
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The invention belongs to the field of bactericides, and particularly relates to a benzoxaborole-1-alcohol compound and a preparation method and application thereof. The benzoxaborole-1-alcohol compound has good bactericidal activity, can effectively control tomato early blight, wheat scab, rice sheath blight disease, strawberry gray mold, apple blotch, cucumber anthracnose and other crop diseases,can produce excellent antibacterial effects at low concentration, and shows good selectivity. The compound is used as a leucyl-tRNA synthetase inhibitor, the evolution difference of aminoacyl-tRNA synthetase of germs and eukaryotes is utilized, and the compound has very high safety to non-target organisms while killing the germs and can be used as a bactericide in agriculture.
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- NOVEL PROCESS FOR THE PREPARATION TAVABOROLE AND ITS INTERMEDIATES
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The present invention provides a novel and improved process for the preparation of Tavaborole of Formula (I) and its pharmaceutically acceptable salts. The present invention also provides novel intermediates and process for the preparation of intermediates used in the preparation of Tavaborole. The present invention also provides an improved process for the preparation of Tavaborole and pharmaceutically acceptable salts thereof, that is commercially and industrially scalable.
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Page/Page column 19
(2019/05/22)
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- Preparation process of antifungal drug tavaborole
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The invention relates to a preparation process of an antifungal drug tavaborole. The preparation process of the antifungal drug tavaborole comprises the following reaction steps: taking 2-bromo-5-fluorobenzaldehyde as a starting material, reacting the 2-bromo-5-fluorobenzaldehyde with pinacol borate in the presence of a palladium catalyst and a solvent to generate 2-pinacol boron-5-fluorobenzaldehyde (TAV-A), and carrying out reduction and ring closure to generate the product tavaborole. In aftertreatment, the PH value of a reaction solution is adjusted by using sig water, and then the tavaborole can be separated out. The preparation process is short in reaction steps, mild and safe in conditions, easy to operate and high in yield, is environmentally friendly, and is suitable for industrial production.
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Paragraph 0026-0031
(2019/04/06)
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- Preparation method of easy-to-purify benzoxaborole antifungal drug
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The invention discloses a preparation method of an easy-to-purify benzoxaborole antifungal drug, which comprises the following steps: (1) a compound I is reduced by sodium borohydride, so that a compound II is obtained; (2) under an alkaline condition, a compound III is obtained from the compound II with DMAP as a catalyst under the protection of triphenylchloromethane; (3) the compound III undergoes bromine-lithium exchange reaction; after triisopropyl borate is added for reaction, hydrolysis is carried out, so that an intermediate is obtained, and the intermediate undergoes deprotection andring closure, and the benzoxaborole antifungal drug shown as a compound IV is obtained. Because the preparation method replaces chloromethyl methyl ether used for hydroxy group protection in the conventional 5-fluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole synthesis route with triphenylchloromethane, a solid protecting group is formed, refinement and purification are easy, the purification processis simplified, the purity of the product is increased, and the production cost is also reduced.
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Paragraph 0016; 0057; 0058-0060; 0064-0066; 0069; 0073-0075
(2018/09/08)
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- PROCESS FOR PREPARATION OF TAVABOROLE
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The present invention relates to process for preparation of tavaborole with high purity. The present invention relates to method of assessing the purity of tavaborole.
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- NOVEL PROCESS FOR THE PREPARATION OF TAVABOROLE, ITS NOVEL POLYMORPHIC FORMS AND THE POLYMORPHS THEREOF
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The invention relates to novel process for preparation of Tavaborole. The invention also relates to novel polymorphic forms of Tavaborole and process for preparation of those polymorphic forms. The invention also relates to process for purification of Tavaborole to obtain the Tavaborole in significantly high yield and substantially pure form.
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Page/Page column 34
(2017/11/15)
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- Preparation method for Tavaborole
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The invention relates to a preparation method for Tavaborole as shown in a formula (I) in the specification. The method comprises the following steps: allowing 3-fluorobenzyl alcohol to react with BCl3 in an organic solvent, and directly subjecting the obtained reaction liquid without the need of purification to a subsequent cyclization reaction. The method has the advantages of mild reaction conditions and easily-controllable industrial production, avoids the use of a noble metal catalyst, and reduces production cost.
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Paragraph 0022; 0034; 0035
(2017/04/28)
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- Scalable, Metal- and Additive-Free, Photoinduced Borylation of Haloarenes and Quaternary Arylammonium Salts
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We report herein a simple, metal- and additive-free, photoinduced borylation of haloarenes, including electron-rich fluoroarenes, as well as arylammonium salts directly to boronic acids. This borylation method has a broad scope and functional group tolerance. We show that it can be further extended to boronic esters and carried out on gram scale as well as under flow conditions.
- Mfuh, Adelphe M.,Doyle, John D.,Chhetri, Bhuwan,Arman, Hadi D.,Larionov, Oleg V.
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supporting information
p. 2985 - 2988
(2016/03/19)
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- Substituent effects on oxidation-induced formation of quinone methides from arylboronic ester precursors
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A series of arylboronic esters containing different aromatic substituents and various benzylic leaving groups (Br or N+Me3Br -) have been synthesized. The substituent effects on their reactivity with H2O2 and formation of quinone methide (QM) have been investigated. NMR spectroscopy and ethyl vinyl ether (EVE) trapping experiments were used to determine the reaction mechanism and QM formation, respectively. QMs were not generated during oxidative cleavage of the boronic esters but by subsequent transformation of the phenol products under physiological conditions. The oxidative deboronation is facilitated by electron-withdrawing substituents, such as aromatic F, NO2, or benzylic N+Me 3Br-, whereas electron-donating substituents or a better leaving group favor QM generation. Compounds containing an aromatic CH 3 or OMe group, or a good leaving group (Br), efficiently generate QMs under physiological conditions. Finally, a quantitative relationship between the structure and activity has been established for the arylboronic esters by using a Hammett plot. The reactivity of the arylboronic acids/esters and the inhibition or facilitation of QM formation can now be predictably adjusted. This adjustment is important as some applications may benefit and others may be limited by QM generation. Tunable quinone methide formation: Aromatic substituents and the benzylic leaving group strongly affect the H 2O2-induced formation of quinone methides (QMs) from arylboronic esters (see scheme). The reactivity of arylboronic esters can be predictably adjusted by varying substituents. Copyright
- Cao, Sheng,Christiansen, Robin,Peng, Xiaohua
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p. 9050 - 9058
(2013/07/26)
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- Synthesis and biological evaluations of P4-benzoxaborole-substituted macrocyclic inhibitors of HCV NS3 protease
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We disclose here a series of P4-benzoxaborole-substituted macrocyclic HCV protease inhibitors. These inhibitors are potent against HCV NS3 protease, their anti-HCV replicon potencies are largely impacted by substitutions on benzoxaborole ring system and P2 groups. P2 2-thiazole-isoquinoline provides best replicon potency. The in vitro SAR studies and in vivo PK evaluations of selected compounds are described herein.
- Ding, Charles Z.,Zhang, Yong-Kang,Li, Xianfeng,Liu, Yang,Zhang, Suoming,Zhou, Yasheen,Plattner, Jacob J.,Baker, Stephen J.,Liu, Liang,Duan, Maosheng,Jarvest, Richard L.,Ji, Jingjing,Kazmierski, Wieslaw M.,Tallant, Matthew D.,Wright, Lois L.,Smith, Gary K.,Crosby, Renae M.,Wang, Amy A.,Ni, Zhi-Jie,Zou, Wuxin,Wright, Jon
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scheme or table
p. 7317 - 7322
(2011/01/12)
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- BORON-CONTAINING SMALL MOLECULES AS ANTI-INFLAMMATORY AGENTS
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Methods of treating anti-inflammatory conditions through the use of boron-containing small molecules are disclosed.
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Page/Page column 41
(2008/06/13)
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- Compounds for the Treatment of Periodontal Disease
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Compounds, compositions and methods are provided which are useful in the treatment of periodontal disease.
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Page/Page column 44-45
(2008/06/13)
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- Hydrolytically-Resistant Boron-Containing Therapeutics And Methods Of Use
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Compositions and methods of use of boron derivatives, including benzoxaboroles, benzazaboroles and benzthiaboroles, as therapeutic agents for treatment of diseases caused by fungi, yeast, bacteria or viruses are disclosed, as well as methods for synthesis of said agents and compositions thereof.
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Page/Page column 59
(2008/06/13)
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- Practical synthesis and applications of benzoboroxoles
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A convenient one-pot synthesis of benzoboroxoles has been developed via the reaction of o-bromobenzyl alcohols with NaH, nBuLi, and B(OiPr)3 followed by acidic hydrolysis. Applications of these benzoboroxoles have been demonstrated in Pd-catalyzed cross-coupling reactions and the protocol has been extended for the synthesis of a chiral benzoboroxole. Exceptionally short synthesis of a potent antifungal agent AN2690 and several of its analogs has also been realized.
- Gunasekera, Dinara S.,Gerold, Dennis J.,Aalderks, Nathan S.,Chandra, J. Subash,Maanu, Christiana A.,Kiprof, Paul,Zhdankin, Viktor V.,Reddy, M. Venkat Ram
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p. 9401 - 9405
(2008/02/13)
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- Boron-containing small molecules
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This invention relates to compounds useful for treating fungal infections, more specifically topical treatment of onychomycosis and/or cutaneous fungal infections. This invention is directed to compounds that are active against fungi and have properties that allow the compound, when placed in contact with a patient, to reach the particular part of the skin, nail, hair, claw or hoof infected by the fungus. In particular the present compounds have physiochemical properties that facilitate penetration of the nail plate.
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Page/Page column 28; 30; 31
(2008/06/13)
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- Discovery of a new boron-containing antifungal agent, 5-fluoro-1,3-dihydro- 1-hydroxy-2,1-benzoxaborole (AN2690), for the potential treatment of onychomycosis
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A structure-activity relationship investigation for a more efficacious therapy to treat onychomycosis, a fungal infection of the toe and fingernails, led to the discovery of a boron-containing small molecule, 5-fluoro-1,3-dihydro- 1-hydroxy-2,1-benzoxaborole (AN2690), which is currently in clinical trials for onychomycosis topical treatment.
- Baker, Stephen J.,Zhang, Yong-Kang,Akama, Tsutomu,Lau, Agnes,Zhou, Huchen,Hernandez, Vincent,Mao, Weimin,Alley,Sanders, Virginia,Plattner, Jacob J.
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p. 4447 - 4450
(2007/10/03)
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- PENTACYCLIC OXEPINES AND DERIVATIVES THEREOF, COMPOSITIONS AND METHODS
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The present invention provides a compound of the formula (I) wherein R1 is -H, -OH, -O(C1-C4 alkyl), -OCOC6H5, -OCO(C1-C6 alkyl), or -OSO2(C2-C6 alkyl); R0, R2 and R3 are each independently -H, -OH, -O(C1-C4 alkyl), -OCOC6H5, -OCO(C1-C6 alkyl), -OSO2(C2-C6 alkyl) or halo; R4 is 1-piperidinyl, 1-pyrrolidinyl, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidinyl, 4-morpholino, dimethylamino, diethylamino, diisopropylamino, or 1-hexamethyleneimino; n is 2 or 3 X is -S- or -HC=CH-; G is -O-, -S-, -SO-, SO2, or -N(R5)-, wherein R5 is -H or C1-C4 alkyl; and Y is -O-, -S-, -NH-, -NMe-, or -CH2-; or a pharmaceutically acceptable salt thereof; pharmaceutical compositions thereof, optionally in combination with estrogen and progestin; methods of inhibiting a disease associated with estrogen deprivation; and methods for inhibiting a disease associated with an aberrant physiological response to endogenous estrogen.
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