Optically active epoxides are versatile synthetic intermediates and asymmetric epoxidation is the most powerful method for their synthesis. Aqueous hydrogen peroxide is clean and atom-efficient and the epoxidation with it has been extensively studied. Thus, rapid advancement of asymmetric epoxidation using hydrogen peroxide has been made in recent years. In this Review de Debut, representative works of asymmetric epoxidation with aqueous hydrogen peroxide including a recent progress are overviewed.

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N-ヘテロ環状カルベン（NHC）骨格の4位に電子供与性の高いMe₃Si-基を導入した配位子を用いて，ルテニウムカルベン錯体[Cl₂(Cy₃P)(4-Me₃Si-IPr) Ru=CHPh] （錯体触媒1, IPr = 1,3-ビス(2,6-ジイソプロピルフェニル)イミダゾール-2-イリデン）を新規に合成し，NMRを用いて分光学的に化合物を同定した。この錯体触媒1について，ジエチルジアリールマロネートの閉環メタセシス反応で触媒性能の評価を行った。錯体触媒1の触媒性能は市販の第一世代グラブス触媒 [Cl₂(Cy₃P)₂Ru=CHPh] を大きく上回るとともに，文献既知のMe₃Si-基を持たない無置換NHCを配位子とする第二世代グラブス触媒 [Cl₂(Cy₃P)(IPr)Ru=CHPh] と同等以上の触媒活性を示した。

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To promote the effective utilization and quality control of single crude drug extract products, the “Application guidance for OTC of (non-Kampo) single crude drug extract products” was published by the Ministry of Health, Labour and Welfare of Japan in December 2015. For further expansion of this guidance, we previously reported the standardization of three single crude drug extracts, which were listed in Non-JP Crude Drug Standards (Non-JPS) 2018. In this study, we report the designed and verified methods for the identification tests and assay of six single crude drug extracts, i.e. Ginseng Extract (1), Red Ginseng Extract (2), Polygala Root Extract (3), Bupleurum Root Extract (4), Peony Root Extract (5), and Citrus Unshiu Peel Extract (6), which were newly listed in Non-JPS 2022, published in March 2022.

Ginsenoside Rg₁ was selected as the marker compound (MC) of 1 and 2 for the identification test by TLC, and ginsenoside Rg₁ and ginsenoside Rb₁ were selected as the MCs of 1 and 2 for the assay by HPLC. Tenuifolin and 3,6’-di-O-sinapoylsucrose were selected as the MCs of 3 for the identification test by TLC and the assay by HPLC, respectively. Saikosaponins a and c were selected as the MCs of 4 for the identification test by TLC. Saikosaponin b₂ was selected as the MC of 4 for the assay using HPLC. Paeoniflorin was selected as the MC of 5 for the identification test using TLC and the assay using HPLC. Hesperidin and narirutin were selected as the MCs of 6 for the identification test using HPLC and hesperidin was selected as the MC of 6 for the assay using HPLC.

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Last year in this symposium, we reported that aryliridium-salen complexes (1 and 2) catalyzed highly enantio- and cis-selective cyclopropanation of conjugated terminal and cis-disubstituted olefins. In the subsequent study, it was found that this cyclopropanation could be applied to cyclopropanation of non-conjugated terminal olefins without diminishing enantio- and cis-selectivity. In addition, we could determine the structure of arylimidium-salen complex 2, which gave a possible explanation for unusual temperature effect presented in the symposium. Asymmetric cyclopropanation of non-conjugated terminal olefins provides a potent tool for preparing optically active cis-disubstituted cyclopropanes that are observed in various natural products. In order to explore this possibility, we tried the synthesis of cyclopropyl fatty acid methyl ester 7 starting from 1-ctene. Asymmetric cyclopropanation of 1-octene gave the cis-cyclopropanecarboxylate 3 in 41 % after the separation of the corresponding trans-isomer by silica gel chromatography. Compound 3 was converted into 7 via four steps in a 57% yield. It has been reported that the enantiomer of 7 can be converted into Lysophosphatidic acid (PHYLPA), a specific inhibitor of DNA polymerase α.

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This paper reports on a method to measure vibrations in various frequency bands caused by cutting or equipment corruption using a MEMS wideband acoustic sensor that can measure vibrations in a wide frequency band from Hz to MHz with a single element. We demonstrated that it was possible to detect the vibration of wide range generated when the tool was broken and or worn by this sensor.

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Ligustrum Fruit is a crude drug derived from the fruit of Ligustrum lucidum W.T. Aiton or L. japonicum Thunb. (Oleaceae). It has several pharmaceutical activities including hepatoprotection, antioxidation and improvement of bone turnover and therefore, it is used as an ingredient in many crude drug products for nutrition fortification. In preparation for the listing of the drug to Non-JP Crude Drug Standards (Non-JPS), we designed an identification test using TLC and identified the marker spot as nuzhenide based on the spectroscopic data including ¹H-, ¹³C-NMR and MS together with the comparison of TLC, LC-MS and NMR with those of the authentic compound.

The established TLC conditions are as follows: chromatographic support, silica gel; developing solvent, EtOAc/MeOH/H₂O (7/2/1); developing length, 7 cm; detection, UV (254 nm) and 1-naphthol-sulphuric acid reagent; R_f value, 0.4 (nuzhenide).

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Enantioenriched epoxides are a useful chiral building block in asymmetric transformatons, and they are also an important morif sometimes found in natural products. Catalytic asymmetric epoxidation of olefins is the most direct and effective route to the optically active epoxides. Herein, we present the development of three chiral titanium catalysts, di-μ-oxo titanium(salan 3) complex, for asymmetric epoxidation of olefins with a green oxidant, aqueous hydrogen peroxide (Figure 1). Di-μ-oxo titanium complex 1 showed high caalytic performance in the epoxidation of terminal, cis-disubstituted and trisubstituted conjugate olefins (Scheme 1). In the epoxidation of 1,2-dihydronaphthalene, the desired epoxide was obtained in 92% yield with >99% ee in the presence of only 0.02 mol% of the catalyst. Aliphatic olefins, which are a challenging substrate in asymmetric epoxidation, were also converted to the epoxides with good to high enantioselectivity. High reactivity of titanium(salalen) 1 rendered asymmetric epoxidation of cis-alkenylsilanes possible, where the epoxysilanes were obtaine with complete enantioselectivity (Scheme 2). We proposed a peroxotitanium complex, which is activated by hydrogen bonding with amino proton, as active species (Figure 2). On the basis of the putative mechanism of the epoxidation with complex 1, we developed more-easily available titanium(salan) complexes which were prepared in situ from Ti(OiPr)_4 and the corresponding salan ligands (scheme 3). In particular, salan ligand 2 bearing ortho-methoxyphenyl groups at the C3 and C3' positions displayed high enantioselectivity in the epoxidation of conjugate olefins (scheme 4). The method could be applied to a gram-scale synthesis without eroding the enantioselectivity. For example, 50.0g of indene was transformed to indene oxide in 75% isolate yield with 98% ee (Scheme 5). Optically active styrene oxide derivatives are an important class of epoxides. However, there were no general and highly enantioselective (more than 95% ee) catalysts for asymmetric epoxidation of styrenes. Even with titanium(salalen) 1 which has two chiral axes and two chiral centers, the ee value observed in the epoxidation of styrene was 93% ee. Thus, we designed novel C_1-symmetric salan ligand 3 derived from naturally occuring α-amino acid proline for the epoxidation (Scheme 6). The in-situ prepared titanium(salan 3) catalyst exhibited high enantioselectivity ranging from 96 to 98% ee in the epoxidation of styrenes with electron-donating and -withdrawing groups (Scheme 7).

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Hampi (反鼻) is an animal crude drug obtained from Gloydius blomhoffii H. Boie and G. brevicaudus Stejneger, which is obtained after removal of the skin and internal organs. It is compounded into many crude drug products, mainly for analeptic effect, and its annual transaction amount in Japan reaches ca. five tons. Therefore, the drug has been standardized by listing it in Non-JP Crude Drug Standards 2018, where Ptyas dhumnades Cantor is defined as the source animal together with G. blomhoffii and G. brevicaudus. In this paper, we report the development of an identification test by TLC in preparation for the listing. Two indicator spots of the test were purified from G. blomhoffii and P. dhumnades using repeated column chromatography. The chemical structures of those 2 spots were elucidated as (i) a mixture of phosphatidylethanolamine (1) and its analogues and (ii) a mixture of lysophosphatidylethanolamine (2) and its analogues based on the comparison of results of TLC, LC/MS, and NMR with those of authentic compounds.

The TLC used silica gel as chromatographic support and an ethyl acetate : ethanol (99.5) : water (1 : 1 : 1) mixture as the developing solvent. The identification test had a developing length of 7 cm, used ninhydrin reagent for visualization, and reported an R_f of 0.7 for both the mixture of phosphatidylethanolamine and its analogues, and the mixture of lysophosphatidylethanolamine and its analogues.

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The relationship between the physical properties of various kinds of lactose on the market and characteristics of their tablets was investigated. For powdered and granular lactoses, the crystallinity, specific surface area, mean particle diameter and water content were determined. The hardness and thickness of tablets prepared with the powdered and granular lactoses were evaluated. For the powdered lactoses, the crystallinity and water content were nearly equal among manufacturers. For the granular lactoses, the crystallinity, specific surface area and water content varied among manufacturers. When the granular lactoses of lower crystallinity than the powdered lactoses were stored at high relative humidity, the crystallinity and water content increased due to crystallization to α-monohydrate. The tablet hardness prepared with the powdered lactoses increased with the increase in specific surface area. In the case of granular lactoses, the tablet hardness decreased linearly with the increase in the crystallinity of the lactose.

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The purpose of the present study is to investigate the effect of loads applied to agitating powder beds on the particle size distribution. Lactose (JP) was used as a test powder bed and was processed under loads ranging from 6.24 to 41.9 g/cm² by a newly developed powder stress mixer. Particle size distribution and flowability of the processed powder was determined. Particle size distribution was determined by an image analysis system that involves optical microscopy. The internal friction coefficient was measured by a direct shear tester. It was found that at the light load (6.24 g/cm²), particles smaller than 74 μm increased and internal friction coefficient slightly increased with an increase of mixing time. At the heavy loads (29.2 g/cm² and 41.9 g/cm²), particles initially smaller than 74 μm became predominant, but further mix processing reduced them. Internal friction coefficient increased initially, but decreased with an increase of mixing time. Under the heavy loads, this is probably due to a quick increase of fine particles and their subsequent agglomeration to form larger particles. Furthermore, it was assumed that there was a critical fine particle size and critical quantity under which the physical properties of the powder bed change significantly.

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The Japan Kampo Medicines Manufacturers Association (JKMA) established "self-imposed limits of residual pesticides for Kampo products, conventional crude drug products, and crude drugs" in 1996 to ensure their safe use. The self-imposed limits were modified twice, and presently, organochlorine, organophosphorus, and pyrethroid classes of pesticides are being regulated. As reported previously, we have been regularly surveying the on-site implementation of self-imposed limits in member companies since 2005. This report presents the findings of our fourth survey for a one-year target period from April 2016 to March 2017. Consequently, the implementation rate of these limits in at least 13,927 samples was 80.0%. Furthermore, all the detected residual pesticides were within the limits. However, the detection values of chlorpyrifos, diphenylamine, linuron, and pentoxazone from crude drugs were beyond the self-imposed limits, and exceeded the maximum residue limit of the positive list under the Food Sanitation Law. However, considering the difference in water contents between fresh foods and crude drugs, the values, except for pentoxazone, were within the maximum residue limit of fresh foods. Moreover, the detection value of pentoxazone was higher than the maximum residue limit, while isofenphos-methyl had no reference value. Therefore, we estimated their safety based on their acceptable daily intake and daily dosages. Subsequently, these values were not problematic for crude drug users. Nevertheless, we will continue to regularly monitor these pesticides to prevent their contamination of crude drugs.

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Dry extract preparations of Kampo medicines for prescription were approved for use approximately 40 years ago in Japan. Presently, most Kampo medicines are prepared in the form of granules with a few being prepared as tablets or capsules. Granule formulations are generally unsuitable for the elderly due to their bulky nature. Although patients and Kampo manufacturers have expressed a need for the introduction of more acceptable granule alternatives, their introduction has been a challenge due to the lack of guidelines based on bioequivalence evaluations for medicines that include multiple chemical components. For resolving this issue, the researchers at the National Institute of Health Sciences initiated a study in 2009 funded by the Ministry of Health, Labour and Welfare. Several ingredients in Kampo extract products and corresponding standard decoctions were detectable and measurable in human plasma, and some compounds have been reported to be promising candidates for application in bioequivalence evaluations of Kampo formulations. The purpose of the present study was to investigate the potential to assess bioequivalence between kakkonto extract granules and tablets on the basis of the “Guidelines for Bioequivalence Testing of Generic Drugs (partial revision, PFSB/ELD Notification No. 0229010 dated February 29, 2012).”

We investigated the pharmacokinetics of ephedrine and pseudoephedrine, which are ingredients derived from Ephedra Herba in kakkonto formulations, following the oral administration of kakkonto extract granules (one pack) and kakkonto extract tablets (eight tablets). The study was conducted as a two-group, two-period, and open-label crossover study in healthy Japanese volunteers. The plasma concentrations of ephedrine and pseudoephedrine following the administration of the drugs were measured using liquid chromatography with tandem mass spectrometry. Subsequently, we calculated their pharmacokinetic parameters and evaluated their bioequivalence. Analysis of variance using the area under the plasma concentration time curve (AUC) and the maximum plasma concentration (C_max) of both ingredients revealed that while AUC indicated bioequivalence, C_max values were significantly different. Plasma concentration levels in both formulations were similar in most volunteers and differed among some volunteers, which was attributed to a high number of tablets per dose as opposed to intra-individual variation. We concluded that ephedrine and pseudoephedrine in kakkonto extracts are good marker compounds for the evaluation of bioequivalence in different forms of kakkonto products.

Our results suggest that the marker compounds exhibiting similarity in pharmacokinetic parameters following the administration of Kampo extract granules and the corresponding standard decoction could be applied as markers for the evaluation of bioequivalence between already-approved Kampo extract granules and novel Kampo products based on the same extract as that of granules.

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従来のN-ヘテロ環状カルベン（NHC）-金属固定化触媒は，窒素上置換基を担体との固定化部位に利用しており，NHC配位子の特徴である窒素上置換基のかさ高さが十分生かせない点に課題があった。我々は，NHCのバックボーン炭素（4位炭素）に着目し，この部位を担体との結合点とする新たな触媒設計を考案した。まず，代表的なNHC配位子であるIPr（1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene）のバックボーン炭素に各種シリル基を導入し，これを配位子としたSi–IPr–Pd錯体触媒を合成した。導入したシリル基の電子特性を調査したところ，電子供与性シリル基の場合，C–Nカップリング反応の触媒活性が向上することを見出した。次に，この知見を展開し，ポリスチレン樹脂にクロロシリル基を有したSi–IPr–Pd錯体触媒を固定化させることで，電子供与性シリル基を担体との結合点とし，かつ窒素上置換基のかさ高さを維持したSi–IPr–Pd錯体固定化触媒の創出に成功した。本固定化触媒はC–Nカップリング反応においてSi–IPr–Pd錯体触媒並みの高活性を発現し，かつ反応後ろ液中における残留Pd量は検出限界以下（<1 ppm）であった。

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Although N-hydroxyamides (1) have been known for over a century, the chemistry of 1 is still relatively unexplored. The scope of the present review is a survey of the recent advances of the chemistry of 1 and its derivatives, particularly of new chemical reactions having synthetic utility in organic synthesis developed mainly in our laboratory. The review is divided into two sections. The first section described great utility of divalent positively-charged nitrogen species generated from 1 in synthesis. Electrophilic intramolecular cyclization with an acylnitrenium ion generated from an N-methoxy- or an N-allyloxy-N-chloroamide with anhydrous zinc acetate in nitromethane gave an N-methoxy- or an N-allyloxy nitrogen heterocyclic compound, deprotection of which led to formation of the corresponding N-hydroxy compound. Treatment of an N-hydroxy- or an N-methoxy-N-arylamide and the corresponding lactam with various reagents results in removal of the hydroxy or methoxy function and introduction of nucleophiles at the ortho or para position of the aromatic ring. These methodologies were successfully applied by us for the synthesis of the alkaloid, eupolauramine and for new oxindoles related to the alkaloid, gelsemine, by others. The second section described great utility of N-alkoxyimidoyl halides (2) synthesized from 1. Compounds 2 were readily transformed to other functions such as aldehydes, cyanides, and oximes. This methodology was successfully applied to the synthesis of ω-N-hydroxy-α-amino acids in optically pure form which were the key intermediates for the synthesis of hydroxamate-containing siderophores.

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In December 2015, the “Application guidance for OTC (non-Kampo) single crude drug extract products” was published by the Ministry of Health, Labour and Welfare (Japan) for the quality control of crude drugs. To further expand on this guidance, we designed and verified methods for the identification tests and assays of three single crude drug extracts: Epimedium Herb Extract (1), Uncaria Hook Extract (2), and Ginger Extract (3) specified in Non-JP Crude Drug Standards (Non-JPS) 2018. Magnoflorine and icariin were selected as the marker compounds of 1 for the identification test using TLC and the assay using HPLC, respectively, and [6]-gingerol was selected for both tests of 3. The marker compounds of 2 were total alkaloids for the identification test using filter paper and rhynchophylline and hirsutine for the assay using HPLC.

Based on the results from this study, we determined both identification tests and assays for these three single crude drug extracts listed in the Non-JPS 2018.

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