Ethyl P-toluenesulfonate Research Articles

Screening potential anaphylactoid components in vinpocetine injection using a high expression Mas-related G-protein-coupled receptor X2 cell membrane chromatography.

Vinpocetine injection is often used in clinical treatment of acute cardiovascular and cerebrovascular diseases. However, it was reported that vinpocetine injection caused allergic reactions in clinical use; therefore, its safety needs urgent attention. Until now, research on its sensitization is rarely reported. Here, the components contained in three vinpocetine injections were examined. It was found that besides vinpocetine, the synthetic raw material vincamine, the excipients benzyl alcohol and ethyl p-toluenesulfonate, and the impurities A, B, C, and D, which are excipients specified in the European Pharmacopoeia, were also present in them. Then the Mas-related G-protein-coupled receptor X2 (MRGPRX2)-HEK293 cell membrane chromatography was used to investigate the affinity of them with MRGPRX2 and found that vinpocetine, vincamine, and impurities A, B, C, and D bind to MRGPRX2. Afterwards, these compounds were further used to investigate the local sensitization ability in vivo. The results showed that vinpocetine, vincamine, and impurity C could induce swelling of the paw and decrease body temperature in mice, but only impurity C could cause local skin mast cell degranulation and serum histamine release increase. In vitro, the results also indicated that impurity C could increase intracellular [Ca2+ ] in MRGPRX2-HEK293 cells, whereas vinpocetine and vincamine did not. Therefore, the impurity C was the potential anaphylactoid component in vinpocetine injection, which may be one of the reasons for the occurrence of allergic reactions in the clinical use of vinpocetine injection. This work provides evidence on the sensitization of impurity C and also contributes to promoting the clinical safety of vinpocetine injection.

Covalent organic nanospheres as a fiber coating for solid-phase microextraction of genotoxic impurities followed by analysis using GC-MS

Covalent organic nanospheres (CONs) were explored as a fiber coating for solid-phase microextraction of genotoxic impurities (GTIs) from active ingredients (AIs). CONs were synthesized by an easy solution-phase procedure at 25 °C. The obtained nanospheres exhibited a high specific surface area, good thermostability, high acid and alkali resistance, and favorable crystallinity and porosity. Two types of GTIs, alkyl halides (1-iodooctane, 1-chlorobenzene, 1-bromododecane, 1,2-dichlorobenzene, 1-bromooctane, 1-chlorohexane, and 1,8-dibromooctane) and sulfonate esters (methyl p-toluenesulfonate and ethyl p-toluenesulfonate), were chosen as target molecules for assessing the performance of the coating. The prepared coating achieved high enhancement factors (5097–9799) for the selected GTIs. The strong affinity between CONs and GTIs was tentatively attributed to π–π and hydrophobicity interactions, large surface area of the CONs, and size-matching of the materials. Combined with gas chromatography-mass spectrometry (GC-MS), the established analytical method detected the GTIs in capecitabine and imatinib mesylate samples over a wide linear range (0.2–200 ng/g) with a low detection limit (0.04–2.0 ng/g), satisfactory recovery (80.03%–109.5%), and high repeatability (6.20%–14.8%) and reproducibility (6.20%–14.1%). Therefore, the CON-coated fibers are promising alternatives for the sensitive detection of GTIs in AI samples.

Trace analysis of residual sulfonate esters in Simvastatin by capillary gas chromatography-mass spectrometry

The development, optimization and validation of a gas chromatography-mass spectrometry (GC-MS) method for trace levels of methylmethanesulfonate (MMS), ethylmethanesulfonate (EMS), methyl-p-toluenesulfonate (Mp-TS) and ethyl-p-toluenesulfonate (Ep-TS) in Simvastatin was presented. The factors affecting the identification and determination were discussed. A capillary column (30 m × 0.25 mm i.d.) coated with 0.25 μm film was used for separation. The calibration curves of four sulfonate esters showed good linearity (R2 > 0.99) within the range of 0.5–10 mg L−1. The optimized method proved to be reproducible (%R.S.D.s less than 6%) and suitable for use with external standard quantitation, and also met basic validation requirements.

A Sensitive and Simple HPLC-UV Method for Trace Level Quantification of Ethyl p-Toluenesulfonate and Methyl p-Toluenesulfonate, Two Potential Genotoxins in Active Pharmaceutical Ingredients

A sensitive and simple HPLC/UV method has been developed and validated for the determination of two potential genotoxic impurities, namely methyl p-toluenesulfonate (MPTS) and ethyl p-toluenesulfonate (EPTS) at trace levels in Pemetrexed sodium API. Applying the concept of threshold of toxicological concern (TTC), a limit of 3 ppm each for both genotoxins was calculated based on the maximum daily dose of API. A reversed phase LC method using UV detection was developed and validated. The method was found to be specific and selective for the application. The limit of detection (LOD) and limit of quantitation (LOQ) for both MPTS and EPTS was found to be 0.15 ppm (0.009 μg mL−1) and 0.5 ppm (0.03 μg mL−1), respectively, with respect to sample concentration. The calibration curves of MPTS and EPTS were linear over the concentration range from LOQ to 6 μg/mL. The method was found to be specific, precise, linear and accurate and has been successfully applied to determine the two genotoxins in commercial batches of the API.

Synthesis and Characterization of Rhenium(V) Complexes Having 3-(4-m-Chlorophenylpiperazin-1-yl)butane-1-thiol as Coligand toward 5HT2ASpecific Radiopharmaceuticals

The development of technetium-99m-labeled imaging agent for brain receptors is still a formidable challenge in radiopharmaceutical research. The specific serotonin receptor-binding imaging agent, particularly the 5-HT2 receptor antagonist, attracts great attention because it is known to be involved in many neurological and psychological diseases including Alzhemier’s disease and depression. Many imaging agents suitable for positron emission tomography bearing C and F as a radiotracer were developed on the basis of known 5HT2A receptor antagonist. Imaging agents for single photon emission computed tomography (SPECT) labeled with I or 125 I were also developed. Preparation of technetium-99m-labeled imaging agent for the 5HT2A receptor stems from mimicking the receptor binding compounds as biologically active molecules (BAMs) which bind to the metals to form proper metal complex with other ligands to accommodate all coordination sites. A novel “3+1” mixed ligand rhenium oxo complex can be generated from the combination of tridentate ligand and monodentate BAM. A few reports describe the synthesis and evaluation of technetium(V) and rhenium(V) complex for 5HT2A serotonin receptor binding based on the ketanserin (1) and its derivatives. A ligand used for BAM based on ketanserin can be designed on the basis of two structural units i.e. quinazoline as part A and phenyl piperidinyl ketone as part B. Either part A or B can be used for BAM while the other part goes as metal binding site. Among two approaches, part B, phenyl piperidinyl ketone site is more favorable for biologically active ligand because it is longer and adjustable. The size and structural similarity to replace part A quinazoline ring is more acceptable and its metal complex with technetium99m showed better imaging agent. Recently ketanserin surrogate 2 showed very selective and potent binding activity toward 5HT2A that may serve as a template to design a new technetium-99m-labelled imaging agent. Triazolopyridin-3one can be replaced by the relatively small metal complex while the pendent 1-alkyl-4-phenylpyrazine is served as a biologically recognizable site. In this study, we synthesized and characterized a novel “3+1” mixed ligand rhenium oxo complex with 2-mercaptoethyl sulfide as a ligand and 3-(4-m-chlorophenyl piperazin1-yl) butane-1-thiol as a biologically active co-ligand. 3-(4-m-Chlorophenyl piperazin-1-yl)butane-1-thiol 4 as a BAM was designed on the basis of prototype 5HT2A serotonin specific antagonist 2 that was originated from ketanserin 1 as its analog. The synthesis of monodentate thiol ligand 4 was planned to achieve by the reductive coupling reaction between 4-mercaptobutane-2-one and 1m-phenylpiperazine. At first, ethyl acetoacetate was protected with ethyleneglycol followed by sequential reactions of ester reduction and tosylation to afford 2-[2-methyl-[1,3]-dioxolane-2yl]ethyl p-toluenesulfonate (5). Tosyl group was replaced by potassium thiolacetate to introduce sulfur that will be ended as binding site to metal. Removal of acetyl group from thiolacetate 6 by carbonate in MeOH did not give the expected free thiol but its dimerized disulfide was formed 7. Then diketone 8 was yielded by treatment of hydrochloric acid in acetone. Reductive cleavage of disulfide at this stage was not quite successful. Instead of reductive amination with two mole equivalents of 1-m-chlorophenylpiperazine coupling

Solvent Effects on the Solvolysis of p-Nitrobenzyl and 3,5-Bis(trifluoromethyl)benzyl p-Toluenesulfonates

Abstract Solvolysis rates of p-nitrobenzyl and 3,5-bis(trifluoromethyl)benzyl p-toluenesulfonates were determined in a wide variety of solvents. The solvent effects were analyzed based on the Winstein–Grunwald equation. The solvent effect on these deactivated benzyl solvolyses failed to give a single linear correlation with the 2-adamantyl YOTs parameter. The lower response to the solvent polarity and the pattern of dispersion for respective binary solvent series can be interpreted in terms of nucleophilic solvent assistance. The application of the equation gave a low m value of 0.4 and a large l of close to unity for both derivatives. Furthermore, the l value is also comparable to that for ethyl p-toluenesulfonate and even close to that for the methyl derivative, which has generally been defined as the standard SN2 substrate.

The absolute configuration of benproperinium dihydrogen phosphate, an antitussive drug.

The (+)- and (-)-enantiomers of benproperinium dihydrogen phosphate, an antitussive drug, have been assigned the R- and S-configurations, respectively, by syntheses of both enantiomers using (S)-2-hydroxypropanoic acid (L-lactic acid) as chiral synthon. The key intermediate, (S)-1-methyl-2-[2-(phenylmethyl)phenoxy]ethyl p-toluenesulfonate, was subjected to an SN2-type reaction with piperidine furnishing (+)-(R)-benproperinium dihydrogen phosphate. (-)-(S)-Benproperinium dihydrogen phosphate was obtained by submitting the same tosylate to two consecutive SN2-type reactions with Br- and piperidine, respectively, acting as nucleophiles.

Condensed thiolane 1,1-dioxide system

Alkylation of trans-N-alkyl(or aryl)-N'-(3-hydroxy-1,1-dioxothiolan-4-yl) thioureas with ethyl p-toluenesulfonate, and the reaction of cyanogen bromide wiht an ethyl p-toluenesulfonate, and the reaction of cyanogen bromide with trans-3-hydroxy-4-aminothiolan-1,1-dioxides have given salts of trans-2-iminoperhydrothieno[3,4-d]-oxazole 5,5-dioxides. Rearrangement of these oxazolidines in the presence of bases afford perhydrothieno[3,4-d]imidazole-2-one 5,5-dioxides.

Reactions of Polyfluoroalkyl o-nitrobenzenesulfonates with 1, 4-Diazabicyclo [2. 2. 2] octane

ボリフルオロアルキル=o-ニトロベンゼンスルホナート [1a～d] と1, 4-ジアザビシクロ[2. 2. 2]ユオクタン(DABCO)との反応を種々の条件下で検討した。ボリフルオロアルキル基の短い [1a,b] はベンゼン中, 35。Cで高収率(93～94%)の1-(ポリフルオロアルキル)-4-アザ-1-アゾニアビシクロ[2. 2. 2]オクタン=o-ニトロベンゼンスルポナート [2a,b-I] を与えたが, ボリフルオロアルキル基の長い [1c,d] は同条件下では反応しなかった。しかし, ベンゼン中, 80。Cでは, いずれのスルホン酸エステルからも4-アザ-1-[2-[4-(ポリフルオロアルキル)-1-ピペラジニル]エチル]4-アザ-1-アゾニアピシクロ[2. 2. 2]オクタン=o-ニトロベンゼンスルポナート [3a～d-I] が生成した。 [1a] とDABCOとの反応は室温, プロトン性溶媒中ではまったく起こらなかったが, 非プロトン性極性溶媒中では反応はゆるやかに進行し [2a-I] のほかに [3a-I] を与えた。ρ-トルエンスルホン酸エチル [5] および2, 2, 2-トリフルオロエチル=ヨージド [7] とDABCOとの反応の結果と [1a] とDABCOとの反応の結果とを比較検討した。合成した第四級アンモニウム塩の二次イオン質量分析(SIMS)では第四級アンモニウムイオンとo-ニトロベンゼンスルホン酸イオンを含むクラスターイオンが観測された。

Reaction of ethyl acetoacetate with p-toluenesulfonic acid: Formation of ethyl isodehydroacetate and/or ethyl p-toluenesulfonate.

Treatment of ethyl acetoacetate with anhydrous p-toluenesulfonic acid at room temperature led to ethyl isodehydroacetate (1) in high yield by acid-catalyzed condensation. On the other hand, in refluxing toluene, the unexpected ethyl ester of p-toluene-sulfonic acid (2) was formed in moderate yield. This constitutes a new direct esterification of arenesulfonic acids.

ChemInform Abstract: A CONVENIENT METHOD OF PREPARING P‐TOLUENESULFONATES OF ETHYL ESTERS OF AMINO ACIDS USING ETHYL P‐TOLUENESULFONATE

AbstractUmsetzen der Aminosäuren (I), (IV) bzw. (VI) mit dem Tosylat (II) in Ethanol ergibt die Aminosäureethylestersalze (III), (V) bzw. (VII).

A Convenient Method of Preparing p-Toluenesulfonates of Ethyl Esters of Amino Acids Using Ethyl p-Toluenesulfonate

Abstract The treatment of amino acids with ethyl p-toluenesulfonate affords the p-toluenesulfonates of the ethyl esters in good yields. Tryptophan ethyl-ester p-toluenesulfonate was also prepared in an 81% yield.

Studies on arylhydrazones of ethyl arylsulfonylglyoxylates

The reaction of arylhydrazones of 4-arylthiosemicarbazides of arylsulfonylglyoxylic acid with ω-bromoacetophenone has given arylhydrazones of N-(3-aryl-4-phenyl-2-thiazolinylidene)hydrazides of arylsulfonylglyoxylic acids. The reaction of ethyl p-toluenesulfonate with o-aminothiophenol and o-phenylenediamine in polyphosphoric acid has given 2-(p-tolylsulfonyl)methylbenzothiazole and 2-(p-tolylsulfonyl)methylbenzimidazole. From 2-(p-tolylsulfonyl)methylbenzothiazole, a styryl and the corresponding carbocyanine with a substituted indoline have been obtained. The considerable hypsochromic shift of the absorption maxima of the latter is explained by the influence of the voluminous electronegative group SO2R in the position α to the heterocyclic nuclei.

A second order kinetics experiment

Investigates the nucleophilic displacement reaction of ethyl p-toluenesulfonate by iodide in acetone.

Rate and Mechanism in the Reactions of Ethyl p-Toluenesulfonate with Water, Hydroxyl Ions and Various Halide Ions1

Rate and Mechanism in the Reactions of Ethyl p-Toluenesulfonate with Water, Hydroxyl Ions and Various Halide Ions¹