A Novel Synthetic Method for Bepotastine, a Histamine H1 Receptor Antagonist

Ha, Tae Ho; Suh, Kwee Hyun; Lee, Gwan Sun

doi:10.5012/bkcs.2013.34.2.549

Cited by 10 publications

(8 citation statements)

References 12 publications

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“…The optical purity of the S-CPMA product reached above 99% ee after recrystallization. 39 Combinatorial libraries were also constructed based on the ten single mutants with enhanced stereoselectivity (Table 1). Fortunately, several excellent R-selective variants were identified in the first round of double mutagenesis (Figure S4D).…”

Section: ■ Results and Discussionsupporting

confidence: 90%

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Structural Insight into Enantioselective Inversion of an Alcohol Dehydrogenase Reveals a “Polar Gate” in Stereorecognition of Diaryl Ketones

et al. 2018

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Diaryl ketones are important building blocks for synthesizing pharmaceuticals and are generally regarded as “difficult-to-reduce” ketones due to the large steric hindrance of their two bulky aromatic side chains. Alcohol dehydrogenase from Kluyveromyces polyspora (KpADH) has been identified as a robust biocatalyst due to its high conversion of diaryl ketone substrate (4-chlorophenyl)(pyridine-2-yl)ketone (CPMK) with a moderate R-selectivity of 82% ee. To modulate the stereoselectivity of KpADH, a “polarity scanning” strategy was proposed, in which six key residues inside and at the entrance of the substrate binding pocket were identified. After iterative combinatorial mutagenesis, variants Mu-R2 and Mu-S5 with enhanced (99.2% ee, R) and inverted (97.8% ee, S) stereoselectivity were obtained. The crystal structures of KpADH and two mutants in complex with NADPH were resolved to elucidate the evolution of enantioselective inversion. Based on MD simulation, Mu-R2–CPMKProR and Mu-S5–CPMKProS were more favorable in the formation of prereaction states. Interestingly, a quadrilateral plane formed by α-carbons of four residues (N136, V161, C237, and G214) was identified at the entrance of the substrate binding pocket of Mu-S5; this plane acts as a “polar gate” for substrates. Due to the discrepancy in charge characteristics between chlorophenyl and pyridine substituents, the pro-S orientation of CPMK is defined when it passes through the “polar gate” in Mu-S5, whereas the similar plane in wild-type is blocked by several aromatic residues. Our result paves the way for engineering stereocomplementary ADH toward bulky diaryl ketones and provides structural insight into the mechanism of stereoselective inversion.

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Section: ■ Results and Discussionsupporting

confidence: 90%

“…After four rounds of ICM, Q136N/F161V/S196G/E214G/S237C (Mu-S5) with 97.8% ee ( S ) was attained. The optical purity of the S -CPMA product reached above 99% ee after recrystallization …”

Section: Resultsmentioning

confidence: 99%

Structural Insight into Enantioselective Inversion of an Alcohol Dehydrogenase Reveals a “Polar Gate” in Stereorecognition of Diaryl Ketones

et al. 2018

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“…The ATH of N -oxide 11 was conducted under the standard conditions, followed by treating with Zn/NH 4 Cl. To our delight, ( S )- 10 was obtained in 97.8% ee ([α] 20 D 45.0 ( c 1.0, EtOH)), which can readily be converted to beptotastine besilate . Most interestingly, the asymmetric induction of N -oxide 11 was opposite to that of 9 .…”

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confidence: 94%

Bifunctional Oxo-Tethered Ruthenium Complex Catalyzed Asymmetric Transfer Hydrogenation of Aryl N-Heteroaryl Ketones

Wang

Zhou

et al. 2017

Org. Lett.

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“…However, to the best of our knowledge, no studies concerning the formation or identification of these 3 new-found process-related impurities have been reported so far. Several syntheses of BTST have been published [7][8][9][10]; the route shown in ▶ Fig. 1 for manufacturing BTST has several advantages such as the use of low-cost materials, a simple preparation process, and good yields [10].…”

Section: Introductionmentioning

confidence: 99%

“…The synthesis route of BTST. Link text: Several syntheses of BTST have been published[7][8][9][10]; the route shown in ▶Fig.1. ▶Fig.…”

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confidence: 99%

Identification, Characterization and HPLC Quantification of Process-Related Impurities in Bepotastine Besilate Bulk Drug

et al. 2019

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Bepotastine besilate (here after referred to as BTST), chemically known as ({d(S)4[4[(4chlorophenyl) (2pyridyl) methoxy] piperidino} butyric acid monobenzene sulphonate), is a second-generation antihistamine drug. To the best of our knowledge, no studies concerning the isolation or identification of process-related impurities have been reported so far. The current study reports the development and validation of a stability-indicating RP-HPLC method for the separation and identification of 5 potential impurities in bepotastine besilate. In this experiment, the structures of 3 process-related impurities were found to be new compounds. They were characterized and confirmed by NMR and MS spectroscopy analyses. These 3 new compounds were proposed to be (S)-4-[(phenyl)-2-pyridinylmethoxy]-1-piperidinebutanoic acid,(Imp-A); 4-[(S)-(4-chlorophenyl)-2-pyridinylmethoxy]-1- piperidinebutyric acid, N-oxide (Imp-B) and (S)-4-[(4- chlorophenyl)-2-pyridinylmethoxy]-1-piperidylethane (Imp-C). In addition, an efficient optimized chromatographic method was performed on a Shimadzu Inertsil C8–3 column (150 mm×4.6 mm, 3 μm) to separate and quantify these 5 impurities. It was using 15 mmol ammonium formate buffer in water (pH adjusted to 3.8 with formic acid) and acetonitrile as the mobile phase in gradient mode. The method was developed to separate and quantify these 5 impurities obtained in the range of 0.05–0.75 μg/mL. It was validated and proven to be selective, accurate and precise and suitable. It is the first publication of identification and characterization data of the 3 new compounds. It is also the first effective HPLC method for separation and quantification of all of process-related impurities in bepotastine besilate.

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A Novel Synthetic Method for Bepotastine, a Histamine H1 Receptor Antagonist

Cited by 10 publications

References 12 publications

Structural Insight into Enantioselective Inversion of an Alcohol Dehydrogenase Reveals a “Polar Gate” in Stereorecognition of Diaryl Ketones

Structural Insight into Enantioselective Inversion of an Alcohol Dehydrogenase Reveals a “Polar Gate” in Stereorecognition of Diaryl Ketones

Bifunctional Oxo-Tethered Ruthenium Complex Catalyzed Asymmetric Transfer Hydrogenation of Aryl N-Heteroaryl Ketones

Identification, Characterization and HPLC Quantification of Process-Related Impurities in Bepotastine Besilate Bulk Drug

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