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Open AccessArticle

Study on Preparation Process of Anticoagulant BAY2433334

by Yanqun Zeng, Guodong Cen, Guanglin Zhou, Xucheng Zhu, Long Huang and Xiaoyu Wang

Molecules 2024, 29(24), 6039; https://doi.org/10.3390/molecules29246039 - 21 Dec 2024

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A new process route suitable for the industrial production of BAY2433334 has been developed in this paper, which avoids the patent limitations of the originator company of BAY2433334 to the preparation of BAY2433334. BAY2433334 is obtained from (2R)-2-aminobutyric acid by esterification, diazotization, condensation reactions, deacetyl deprotection, activation reactions, and Mitsunobu reactions. This method is simple to operate, and the raw materials are inexpensive and readily available. Simultaneously, the product quality is very high; few O-alkylated impurities are generated during the reaction, with a high N-alkylated product/O-alkylated product ratio (above 35–45:1). As a result, the ee value is greater than 99%, which means that there are very few isomers present such that no chiral resolution is required, which greatly reduces the cost. Full article

(This article belongs to the Section Medicinal Chemistry)

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21 pages, 3673 KB

Open AccessEditor’s ChoiceArticle

5-Aryl-1,3,4-oxadiazol-2-amines Decorated with Long Alkyl and Their Analogues: Synthesis, Acetyl- and Butyrylcholinesterase Inhibition and Docking Study

by Václav Pflégr, Šárka Štěpánková, Katarína Svrčková, Markéta Švarcová, Jarmila Vinšová and Martin Krátký

Pharmaceuticals 2022, 15(4), 400; https://doi.org/10.3390/ph15040400 - 25 Mar 2022

Cited by 14 | Viewed by 4869

Abstract

2,5-Disubstituted 1,3,4-oxadiazoles are privileged versatile scaffolds in medicinal chemistry that have exhibited diverse biological activities. Acetyl- (AChE) and butyrylcholinesterase (BChE) inhibitors are used, e.g., to treat dementias and myasthenia gravis. 5-Aryl-1,3,4-oxadiazoles decorated with dodecyl linked via nitrogen, sulfur or directly to this heterocycle have been designed as potential inhibitors of AChE and BChE. They were prepared from commercially available or in-house prepared hydrazides by reaction with dodecyl isocyanate to form hydrazine-1-carboxamides 2 (yields 67–98%) followed by cyclization using p-toluenesulfonyl chloride and triethylamine in 41–100% yields. Thiadiazole isostere was also synthesized. The derivatives were screened for inhibition of AChE and BChE using Ellman’s spectrophotometric method. The compounds showed a moderate dual inhibition with IC₅₀ values of 12.8–99.2 for AChE and from 53.1 µM for BChE. All the heterocycles were more efficient inhibitors of AChE. The most potent inhibitor, N-dodecyl-5-(pyridin-4-yl)-1,3,4-thiadiazol-2-amine 3t, was subjected to advanced reversibility and type of inhibition evaluation. Structure–activity relationships were identified. Many oxadiazoles showed lower IC₅₀ values against AChE than established drug rivastigmine. According to molecular docking, the compounds interact non-covalently with AChE and BChE and block entry into enzyme gorge and catalytic site, respectively. Full article

(This article belongs to the Section Medicinal Chemistry)

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12 pages, 1453 KB

Open AccessArticle

Determination of Glyphosate and AMPA in Food Samples Using Membrane Extraction Technique for Analytes Preconcentration

by Katarzyna Gębura, Piotr P. Wieczorek and Anna Poliwoda

Membranes 2022, 12(1), 20; https://doi.org/10.3390/membranes12010020 - 24 Dec 2021

Cited by 5 | Viewed by 3854

Abstract

The method for determining glyphosate (NPG) and its metabolite AMPA (aminomethyl phosphonic acid) in solid food samples using UAE-SLM-HPLC–PDA technique was developed. Firstly, ultrasonic-assisted solvent extraction (UAE) and protein precipitation step were used for the analyte isolation. Then, the supernatant was evaporated to dryness and redissolved in distilled water (100 mL). The obtained solution was alkalized to pH 11 (with 1 M NaOH) and used directly as donor phase in SLM (supported liquid membrane) extraction. The SLM extraction was performed using 2 M NaCl (5 mL) as an acceptor phase. The flow rate of both phases (donor and acceptor) was set at 0.2 mL/min. The membrane extraction took 24 h but did not require any additional workload. Finally, the SLM extracts were analyzed using the HPLC technique with photo-diode array detector (PDA) and an application of pre-column derivatization with p-toluenesulfonyl chloride. Glyphosate residues were determined in food samples of walnuts, soybeans, barley and lentil samples. The LOD values obtained for the studied food were 0.002 μg g⁻¹ and 0.021 μg g⁻¹ for NPG and AMPA, respectively. Recoveries values ranged from 32% to 69% for NPG, 29% to 56% for AMPA and depended on the type of sample matrix. In the case of buckwheat and rice flour samples, the content of NPG and AMPA was below the detection level of a used analytical method. Full article

(This article belongs to the Special Issue Advances in Supported Liquid Membranes)

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12 pages, 18130 KB

Open AccessArticle

Esterification of Cellulose with Long Fatty Acid Chain through Mechanochemical Method

by Jacqueline Lease, Tessei Kawano and Yoshito Andou

Polymers 2021, 13(24), 4397; https://doi.org/10.3390/polym13244397 - 15 Dec 2021

Cited by 50 | Viewed by 9740

Abstract

Mechanochemical reaction, a green synthetic esterification route was utilized to prepare long-chain cellulose esters from microcrystalline cellulose. The influence of reaction conditions such as reaction temperature and time were elucidated. Only low dosage of oleic acid, 1-butyl-3-metylimidazolium acetate, and p-toluenesulfonyl chloride were required. The success of modification reaction was confirmed by Fourier transforms infrared spectroscopy as a new absorbance peak at 1731 cm⁻¹ was observed, which indicated the formation of carbonyl group (C=O). Solid-state nuclear magnetic resonance was also performed to determine the structural property and degree of substitution (DS) of the cellulose oleate. Based on the results, increasing reaction temperature and reaction time promoted the esterification reaction and DS. DS values of cellulose oleates slightly decreased after 12 h reaction time. Besides, X-ray diffraction analysis showed the broadening of the diffraction peaks and thermal stability decreased after esterification. Hence, the findings suggested that grafting of oleic acid’s aliphatic chain onto the cellulose backbone lowered the crystallinity and thermal stability. Full article

(This article belongs to the Special Issue Bio-Based Materials: Contribution to Advancing Circular Economy)

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7 pages, 149 KB

Open AccessArticle

Synthesis of the Key Intermediate of Coenzyme Q₁₀

by Fan-Song Mu, Meng Luo, Yu-Jie Fu, Xuan Zhang, Ping Yu and Yuan-Gang Zu

Molecules 2011, 16(5), 4097-4103; https://doi.org/10.3390/molecules16054097 - 18 May 2011

Cited by 9 | Viewed by 8124

Abstract

(2’E)-1-(3-methyl-4-p-toluenesulfonyl-2-butene)-6-methyl-2,3,4,5-tetramethoxybenzene (4) is the key intermediate in the synthesis of coenzyme Q₁₀ via a coupling reaction with solanesyl bromide. In this paper, we report a simple and effective synthesis of compound 4, starting with the readily available and inexpensive precursors p-toluenesulfonyl chloride (TsCl) and isoprene to obtain (2E)-1-p-toluenesulfonyl-2-methyl-4-hydroxy-2-butene (3) by addition, esterification and hydrolysis. Application of the Friedel-Crafts alkylation to compound 3, followed by the addition of 2,3,4,5-tetramethoxytoluene (TeMT), assembled the two parts into compound 4. The key parameters of each reaction were optimized at the same time, and the four total operations needed to produced compound 4 had a 27.9% overall yield under the optimized conditions. The structures of the compounds were characterized by ¹H-NMR, IR and MS. This alternative process has the potential to be used for large-scale process. Full article

(This article belongs to the Section Organic Chemistry)

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