176022-47-2Relevant articles and documents
Characterization of Photodegradation Products of Bepotastine Besilate and In Silico Evaluation of Their Physicochemical, Absorption, Distribution, Metabolism, Excretion and Toxicity Properties
Singh, Dilip Kumar,Sahu, Archana,Wani, Aabid Abdullah,Bharatam, Prasad V.,Chakraborti, Asit K.,Giri, Sanjeev,Singh, Saranjit
, p. 1883 - 1895 (2020)
Bepotastine (BPT) is a H1-receptor antagonist. It is used as a besilate salt in ophthalmic solution for allergic conjunctivitis and orally for the treatment of allergic rhinitis and urticaria/pruritus. Its systematic forced degradation study is unreported. The same was carried out in different conditions prescribed by International Conference on Harmonisation. The stressed solutions were subjected to reversed phase liquid chromatographic analysis, and BPT was observed to be labile under photobasic condition only, yielding 5 photodegradation products. The structures of the latter were elucidated from data generated by liquid chromatography–high-resolution mass spectrometry and multistage mass spectrometry. Of the 5, 4 products were further isolated and subjected to nuclear magnetic resonance spectroscopy to justify the proposed structures. Two of them, with similar accurate mass, were additionally and unambiguously characterized from their heteronuclear multiple bond correlation data, hydrogen deuterium exchange mass data, and quantum chemical analysis using density functional theory calculations. One degradation product had a structure that could only be explained by unusual rearrangement involving conversions of N-oxide into hydroxylamine, similar to Meisenheimer rearrangement. The physicochemical, as well as absorption, distribution, metabolism, excretion, and toxicity properties of BPT and its characterized photodegradation products were evaluated in silico by ADMET Predictor software.
Amino alcohols using the optically active amino alcohol derivative bi- Nord complex boron - -
-
Paragraph 0064; 0071-0076; 0287-0288; 0291-0032, (2021/04/16)
Disclosed are an amino alcohol-boron-binol complex as an intermediate, including Complex 3-1-1 shown below, and a method for preparing an optically active amino alcohol by using the same, wherein a racemic amino alcohol is resolved in an enationselective manner using a boron compound and a (R)- or (S)-binol, whereby an amino alcohol derivative with high optical purity can be prepared at high yield.
Electronic Effect-Guided Rational Design of Candida antarctica Lipase B for Kinetic Resolution Towards Diarylmethanols
Li, Dan-Yang,Lou, Yu-Jiao,Xu, Jian,Chen, Xiao-Yang,Lin, Xian-Fu,Wu, Qi
, p. 1867 - 1872 (2021/02/12)
Herein, we developed an electronic effect-guided rational design strategy to enhance the enantioselectivity of Candida antarctica lipase B (CALB) mutants towards bulky pyridyl(phenyl)methanols. Compared to W104A mutant previously reported with reversed S-stereoselectivity toward sec-alcohols, three mutants (W104C, W104S and W104T) displayed significant improvement of S-enantioselectivity in the kinetic resolution (KR) of various phenyl pyridyl methyl acetates due to the increased electronic effects between pyridyl and polar residues. The electronic effects were also observed when mutating other residues surrounding the stereospecificity pocket of CALB, such as T42A, S47A, A281S or A281C, and can be used to manipulate the stereoselectivity. A series of bulky pyridyl(phenyl) methanols, including S-(4-chlorophenyl)(pyridin-2-yl) methanol (S-CPMA), the intermediate of bepotastine, were obtained in good yields and ee values. (Figure presented.).
Engineering an alcohol dehydrogenase with enhanced activity and stereoselectivity toward diaryl ketones: Reduction of steric hindrance and change of the stereocontrol element
Chen, Rong,Huang, Jiankun,Meng, Xiangguo,Shao, Lei,Wu, Kai,Yang, Zhijun
, p. 1650 - 1660 (2020/04/09)
Steric hindrance in the binding pocket of an alcohol dehydrogenase (ADH) has a great impact on its activity and stereoselectivity simultaneously. Due to the subtle structural difference between two bulky phenyl substituents, the asymmetric synthesis of diaryl alcohols by bioreduction of diaryl ketones is often hindered by the low activity and stereoselectivity of ADHs. To engineer an ADH with practical properties and to investigate the molecular mechanism behind the asymmetric biocatalysis of diaryl ketones, we engineered an ADH from Lactobacillus kefiri (LkADH) to asymmetrically catalyse the reduction of 4-chlorodiphenylketones (CPPK), which are not catalysed by the wild type (WT) enzyme. Mutants seq1-seq5 with gradually increased activity and stereoselectivity were obtained through iterative "shrinking mutagenesis." The final mutant seq5 (Y190P/I144V/L199V/E145C/M206F) demonstrated the highest activity and excellent stereoselectivity of >99% ee. Molecular simulation analyses revealed that mutations may enhance the activity by eliminating steric hindrance, inducing a more open binding loop and constructing more noncovalent interactions. The pro-R pose of CPPK with a halogen bond formed a pre-reaction conformation more easily than the pro-S pose, resulting in the high ee of (R)-CPPO in seq5. Moreover, different halogen bonds formed due to the different positions of chlorine substituents, resulting in opposite substrate binding orientation and stereoselectivity. Therefore, the stereoselectivity of seq5 was inverted toward ortho- rather than para-chlorine substituted ketones. These results indicate that the stereocontrol element of LkADH was changed to recognise diaryl ketones after steric hindrance was eliminated. This study provides novel insights into the role of steric hindrance and noncovalent bonds in the determination of the activity and stereoselectivity of enzymes, and presents an approach producing key intermediates of chiral drugs with practical potential.
Molecular switch manipulating Prelog priority of an alcohol dehydrogenase toward bulky-bulky ketones
Xu, Guochao,Dai, Wei,Wang, Yue,Zhang, Lu,Sun, Zewen,Zhou, Jieyu,Ni, Ye
, (2019/12/27)
Structure-guided rational design revealed the molecular switch manipulating the Prelog and anti-Prelog priorities of an NADPH-dependent alcohol dehydrogenase toward prochiral ketones with bulky and similar substituents. Synergistic effects of unconserved residues at 214 and 237 in small and large substrate binding pockets were proven to be vital in governing the stereoselectivity. The ee values of E214Y/S237A and E214C/S237 G toward (4-chlorophenyl)-(pyridin-2-yl)-methanone were 99.3% (R) and 78.8% (S) respectively. Substrate specificity analysis revealed that similar patterns were also found with (4’-chlorophenyl)-phenylmethanone, (4’-bromophenyl)-phenylmethanone and (4’-nitrophenyl)-phenylmethanone. This study provides valuable evidence for understanding the molecular mechanism on enantioselective recognition of prochiral ketones by alcohol dehydrogenase.
Highly Enantioselective Hydrogenation of Non- ortho-Substituted 2-Pyridyl Aryl Ketones via Iridium- f-Diaphos Catalysis
Nian, Sanfei,Ling, Fei,Chen, Jiachen,Wang, Ze,Shen, Haiwei,Yi, Xiao,Yang, Yun-Fang,She, Yuanbin,Zhong, Weihui
supporting information, p. 5392 - 5396 (2019/08/01)
This work disclosed a highly enantioselective hydrogenation of non-ortho-substituted 2-pyridyl aryl ketones via Ir/f-diaphos catalysis. This catalytic system allows for full control over the configuration of the stereocenter, affording two enantiomers of the desired products with extremely high enantioselectivity (up to >99% ee in most cases) and excellent reactivity (TON of up to 19600, TOF of 1633 h-1) under mild conditions. Density functional theory calculations and control experiments revealed that the relay hydrogen bonding among the solvent isopropanol, substrate, and ligand is crucial for high ee's.
Preparation technology of bepotastine medical intermediate
-
Page/Page column 9-14, (2019/06/30)
The invention discloses a preparation technology of a bepotastine medical intermediate. The technology comprises the following processes: under an argon atmosphere and 0 to 60 DEG C, adding a metal Mcomplex and a chiral ligand L into solvent A, and stirring and reacting for 0.5 to 6 hours to prepare a catalyst [M]/L, wherein metal M is Ru, Rh, Ir or Pd; adding (4-chlorophenyl)(pyridin-2-yl)ketone, the prepared catalyst [M]/L, solvent B and alkali into an autoclave, and reacting for 2 to 24 hours under the temperature of 0 to 100 DEG C and the hydrogen pressure of 0.1 to 10.0 MPa; after a reaction is completed, performing vacuum concentration on reaction liquid to recover the solvent B; and then adding a proper amount of water, performing extraction by ethyl acetate, performing liquid separation to obtain an organic phase and a water phase, performing drying and desolvation on the organic phase to prepare (S)-(4-chlorophenyl)(pyridin-2-yl)methanol, namely the bepotastine medical intermediate. Compared with a conventional technology for preparing the (S)-(4-chlorophenyl)(pyridin-2-yl)methanol by a chiral separation method, a method involved in the invention has the characteristics that the consumption of the catalyst is low; the yield and an ee (enantiomeric excess) value are high; and the like; in addition, reaction conditions are mild; the operation is simple and convenient; and industrial production is easy to realize.
Conformational Dynamics-Guided Loop Engineering of an Alcohol Dehydrogenase: Capture, Turnover and Enantioselective Transformation of Difficult-to-Reduce Ketones
Liu, Beibei,Qu, Ge,Li, Jun-Kuan,Fan, Wenchao,Ma, Jun-An,Xu, Yan,Nie, Yao,Sun, Zhoutong
supporting information, p. 3182 - 3190 (2019/05/15)
Directed evolution of enzymes for the asymmetric reduction of prochiral ketones to produce enantio-pure secondary alcohols is particularly attractive in organic synthesis. Loops located at the active pocket of enzymes often participate in conformational changes required to fine-tune residues for substrate binding and catalysis. It is therefore of great interest to control the substrate specificity and stereochemistry of enzymatic reactions by manipulating the conformational dynamics. Herein, a secondary alcohol dehydrogenase was chosen to enantioselectively catalyze the transformation of difficult-to-reduce bulky ketones, which are not accepted by the wildtype enzyme. Guided by previous work and particularly by structural analysis and molecular dynamics (MD) simulations, two key residues alanine 85 (A85) and isoleucine 86 (I86) situated at the binding pocket were thought to increase the fluctuation of a loop region, thereby yielding a larger volume of the binding pocket to accommodate bulky substrates. Subsequently, site-directed saturation mutagenesis was performed at the two sites. The best mutant, where residue alanine 85 was mutated to glycine and isoleucine 86 to leucine (A85G/I86L), can efficiently reduce bulky ketones to the corresponding pharmaceutically interesting alcohols with high enantioselectivities (～99% ee). Taken together, this study demonstrates that introducing appropriate mutations at key residues can induce a higher flexibility of the active site loop, resulting in the improvement of substrate specificity and enantioselectivity. (Figure presented.).
Two enantiocomplementary ephedrine dehydrogenases from arthrobacter sp. TS-15 with broad substrate specificity
Shanati, Tarek,Lockie, Cameron,Beloti, Lilian,Grogan, Gideon,Ansorge-Schumacher, Marion B.
, p. 6202 - 6211 (2019/08/15)
The recently identified pseudoephedrine and ephedrine dehydrogenases (PseDH and EDH, respectively) from Arthrobacter sp. TS-15 are NADH-dependent members of the oxidoreductase superfamily of short-chain dehydrogenases/reductases (SDRs). They are specific for the enantioselective oxidation of (+)-(S) N-(pseudo)ephedrine and (-)-(R) N-(pseudo)ephedrine, respectively. Anti-Prelog stereospecific PseDH and Prelog-specific EDH catalyze the regio- A nd enantiospecific reduction of 1-phenyl-1,2-propanedione to (S)-phenylacetylcarbinol and (R)-phenylacetylcarbinol with full conversion and enantiomeric excess of >99%. Moreover, they perform the reduction of a wide range of aryl-aliphatic carbonyl compounds, including ketoamines, ketoesters, and haloketones, to the corresponding enantiopure alcohols. The highest stability of PseDH and EDH was determined to be at a pH range of 6.0-8.0 and 7.5-8.5, respectively. PseDH was more stable than EDH at 25 °C with half-lives of 279 and 38 h, respectively. However, EDH is more stable at 40 °C with a 2-fold greater half-life than at 25 °C. The crystal structure of the PseDH-NAD+ complex, refined to a resolution of 1.83 ?, revealed a tetrameric structure, which was confirmed by solution studies. A model of the active site in complex with NAD+ and 1-phenyl-1,2-propanedione suggested key roles for S143 and W152 in recognition of the substrate and positioning for the reduction reaction. The wide substrate spectrum of these dehydrogenases, combined with their regio- A nd enantioselectivity, suggests a high potential for the industrial production of valuable chiral compounds.
A (S)- phenyl (pyridine -2 - yl) methanol derivative preparation method (by machine translation)
-
Paragraph 0094-0100, (2019/07/04)
The invention discloses a (S)- (pyridine - 2 - yl) phenyl methanol derivatives of the preparation method, the process is: in the argon atmosphere and 10 - 40 °C temperature, metal M complex with a chiral ligand L* In A added to the solvent, stirring the reaction 0.5 - 6 hours, to obtain the catalyst [M]/ L* ; The metal M in the complex metal M is Ru, Rh, Pd Ir or in any of the a; to the autoclave is sequentially added in the phenyl (pyridin - 2 - yl) methanone derivatives, the obtained catalyst [M]/ L* , Solvent B and alkali, for 0 - 100 °C temperature and 0.1 - 10.0 mpa of reaction under a hydrogen pressure of 2 - 24 hours, after the reaction, the reaction solution concentrated under reduced pressure to recover solvent B, add water, extracted with ethyl acetate, the organic phase and aqueous phase liquid, drying of the organic phase, desolvation prepared (S)- (pyridine - 2 - yl) phenyl methanol derivatives. The catalyst of the present invention asymmetric hydrogenation reaction, a reaction product of high yield, high enantio-selectively generating (S)- (pyridine - 2 - yl) phenyl methanol derivatives, in the ee value of 99% or more. (by machine translation)
