- Mass spectrometric directed system for the continuous-flow synthesis and purification of diphenhydramine
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A highly integrated approach to the development of a process for the continuous synthesis and purification of diphenhydramine is reported. Mass spectrometry (MS) is utilized throughout the system for on-line reaction monitoring, off-line yield quantitation, and as a reaction screening module that exploits reaction acceleration in charged microdroplets for high throughput route screening. This effort has enabled the discovery and optimization of multiple routes to diphenhydramine in glass microreactors using MS as a process analytical tool (PAT). The ability to rapidly screen conditions in charged microdroplets was used to guide optimization of the process in a microfluidic reactor. A quantitative MS method was developed and used to measure the reaction kinetics. Integration of the continuous-flow reactor/on-line MS methodology with a miniaturized crystallization platform for continuous reaction monitoring and controlled crystallization of diphenhydramine was also achieved. Our findings suggest a robust approach for the continuous manufacture of pharmaceutical drug products, exemplified in the particular case of diphenhydramine, and optimized for efficiency and crystal size, and guided by real-Time analytics to produce the agent in a form that is readily adapted to continuous synthesis.
- Loren, Bradley P.,Wleklinski, Michael,Koswara, Andy,Yammine, Kathryn,Hu, Yanyang,Nagy, Zoltan K.,Thompson, David H.,Cooks, R. Graham
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Read Online
- Spectrophotometric method for the determination, validation, spectroscopic and thermal analysis of diphenhydramine in pharmaceutical preparation
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A sensitive, simple and rapid spectrophotometric method was developed for the determination of diphenhydramine in pharmaceutical preparation. The method was based on the charge-transfer complex of the drug, as n-electron donor, with 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ), as π-acceptor. The formation of this complex was also confirmed by UV-vis, FTIR and 1H NMR spectra techniques and thermal analysis. The proposed method was validated according to the ICH guidelines with respect to linearity, limit of detection, limit of quantification, accuracy, precision, recovery and robustness. The linearity range for concentrations of diphenhydramine was found to be 12.5-150 μg/mL with acceptable correlation coefficients. The detection and quantification limits were found to be 2.09 and 6.27 μg/mL, respectively. The proposed and references methods were applied to the determination of drug in syrup. This preparation were also analyzed with an reference method and statistical comparison by t- and F-tests revealed that there was no significant difference between the results of the two methods with respect to mean values and standard deviations at the 95% confidence level.
- Ulu, Sevgi Tatar,Elmali, Fikriye Tuncel
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Read Online
- Photocatalytic Water-Splitting Coupled with Alkanol Oxidation for Selective N-alkylation Reactions over Carbon Nitride
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Photocatalytic water splitting technology (PWST) enables the direct use of water as appealing “liquid hydrogen source” for transfer hydrogenation reactions. Currently, the development of PWST-based transfer hydrogenations is still in an embryonic stage. Previous reports generally centered on the rational utilization of the in situ generated H-source (electrons) for hydrogenations, in which photogenerated holes were quenched by sacrificial reagents. Herein, the fully-utilization of the liquid H-source and holes during water splitting is presented for photo-reductive N-alkylation of nitro-aromatic compounds. In this integrate system, H-species in situ generated from water splitting were designed for nitroarenes reduction to produce amines, while alkanols were oxidized by holes for cascade alkylating of anilines as well as the generated secondary amines. More than 50 examples achieved with a broad range scope validate the universal applicability of this mild and sustainable coupling approach. The synthetic utility of this protocol was further demonstrated by the synthesis of existing pharmaceuticals via selective N-alkylation of amines. This strategy based on the sustainable water splitting technology highlights a significant and promising route for selective synthesis of valuable N-alkylated fine chemicals and pharmaceuticals from nitroarenes and amines with water and alkanols.
- Xu, Yangsen,Zhang, Zhaofei,Qiu, Chuntian,Chen, Shaoqin,Ling, Xiang,Su, Chenliang
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p. 582 - 589
(2020/12/09)
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- Systems and methods for synthesizing chemical products, including active pharmaceutical ingredients
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Systems and methods for synthesizing chemical products, including active pharmaceutical ingredients, are provided. Certain of the systems and methods described herein are capable of manufacturing multiple chemical products without the need to fluidically connect or disconnect unit operations when switching from one making chemical product to making another chemical product.
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Page/Page column 33-35
(2020/12/14)
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- Organic synthesis in a modular robotic system driven by a chemical programming language
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The synthesis of complex organic compounds is largely a manual process that is often incompletely documented. To address these shortcomings, we developed an abstraction that maps commonly reported methodological instructions into discrete steps amenable to automation. These unit operations were implemented in a modular robotic platform by using a chemical programming language that formalizes and controls the assembly of the molecules. We validated the concept by directing the automated system to synthesize three pharmaceutical compounds, diphenhydramine hydrochloride, rufinamide, and sildenafil, without any human intervention. Yields and purities of products and intermediates were comparable to or better than those achieved manually. The syntheses are captured as digital code that can be published, versioned, and transferred flexibly between platforms with no modification, thereby greatly enhancing reproducibility and reliable access to complex molecules.
- Steiner, Sebastian,Wolf, Jakob,Glatzel, Stefan,Andreou, Anna,Granda, Jaros?aw M.,Keenan, Graham,Hinkley, Trevor,Aragon-Camarasa, Gerardo,Kitson, Philip J.,Angelone, Davide,Cronin, Leroy
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- Method for preparing toluene benzyl phenyl substituted compound
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In order to overcome the shortcomings of the prior art, the invention provides a method for preparing a toluene benzyl phenyl substituted compound. According to the method, first a reaction substrateand an attack reagent are added in a reaction vessel and mixed; a catalyst is added to the mixture and evenly mixed; the evenly mixed material reacts for 12-48 h at 70-110 DEG C; finally, a solvent isremoved, and a product is purified, to obtain the toluene benzyl substituted compound. The reaction substrate is a compound containing a phenyl group and having at least one alpha hydrogen attached to the phenyl group; and the attack reagent is phenylboronic acid. The catalyst is a mixture of di-tert-butyl peroxide and nickel acetylacetonate. By synthesizing 2 kg of diphenhydramine hydrochloridethrough the synthetic method, the cost can be reduced by 150000 yuan.
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Paragraph 0024; 0025; 0026; 0027
(2018/03/26)
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- Preparation method of phenyl mono-substituted phenyl alpha-hydrogen compound
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In order to overcome the defects of the prior art, the invention provides a preparation method of a phenyl mono-substituted phenyl alpha-hydrogen compound. The preparation method comprises: adding a reaction matrix and an attack reagent into a reaction container, and mixing; adding a catalyst into the mixture, and mixing well; allowing reaction of the obtained mixture at 80-120 DEG C for 12-48 hours; removing a solvent, purifying the product to obtain the phenyl mono-substituted phenyl alpha-hydrogen substitution product. The reaction matrix is a compound containing phenyl that is linked with at least one alpha-hydrogen; the attack reagent is pinacol phenylborate. The catalyst is a mixture of di-tert-butyl peroxide and cobalt acetylacetonate. The synthesis of 1000 g of diphenhydramine hydrochloride via a synthetic method may bring a cost saving of 50000 RMB.
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Paragraph 0031; 0032; 0033; 0035; 0037
(2018/01/14)
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- π-Conjugated Triazenes: Intermediates That Undergo Oxidation and Substitution Reactions
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Novel reactivity for π-conjugated triazenes is herein reported. This observed and unprecedented triazene reactivity gave access to oxidation and substitution reactions. These transformations include successful synthesis of aldehydes, ketones, ethers, and sulfides from readily available organic azides via π-conjugated triazene intermediates. Notably, the afforded adducts were obtained in good yields, at room temperature, and in the absence of added metal catalysts.
- Barragan, Enrique,Bugarin, Alejandro
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p. 1499 - 1506
(2017/02/10)
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- Method for preparing diphenhydramine
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The invention relates to a preparation method of diphenhydramine, which takes benzhydrol and dimethylaminoethanol as raw materials, under existence of dibutyltin oxide and ion liquid compound, benzhydrol and dimethylaminoethanol are subjected to an intermolecular dehydration reaction to obtain diphenhydramine. The method has the advantages of simple preparation technology, mild reaction condition, low cost, high product yield and high purity.
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Paragraph 0023-0034
(2019/04/27)
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- Ionic fluids containing both strongly and weakly interacting ions of the same charge have unique ionic and chemical environments as a function of ion concentration
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Liquid multi-ion systems made by combining two or more salts can exhibit charge ordering and interactions not found in the parent salts, leading to new sets of properties. This is investigated herein by examining a liquid comprised of a single cation, 1-ethyl-3-methylimidazolium ([C2mim]+), and two anions with different properties, acetate ([OAc]-) and bis(trifluoromethylsulfonyl)imide ([NTf2]-). NMR and IR spectroscopy indicate that the electrostatic interactions are quite different from those in either [C2mim][OAc] or [C2mim][NTf2]. This is attributed to the ability of [OAc]- to form complexes with the [C2mim]+ ions at greater than 1:1 stoichiometries by drawing [C2mim]+ ions away from the less basic [NTf2]- ions. Solubility studies with molecular solvents (ethyl acetate, water) and pharmaceuticals (ibuprofen, diphenhydramine) show nonlinear trends as a function of ion content, which suggests that solubility can be tuned through changes in the ionic compositions.
- Wang, Hui,Kelley, Steven P.,Brantley, Jimmy W.,Chatel, Gregory,Shamshina, Julia,Pereira, Jorge F. B.,Debbeti, Varun,Myerson, Allan S.,Rogers, Robin D.
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p. 993 - 1002
(2015/04/14)
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- General catalytic methylation of amines with formic acid under mild reaction conditions
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A general catalytic protocol for the methylation of amines has been developed applying, for the first time, formic acid as the C1 building block and silanes as reducing agents. A broad range of aromatic and aliphatic, both primary and secondary, amines has been converted to the corresponding tertiary amines including [N-13C]-labelled drugs in good to excellent yields under mild conditions. Methylation made easy: A general catalytic protocol for the methylation of amines has been developed applying, for the first time, formic acid as the C1 building block and silanes as reducing agents. A broad range of aromatic and aliphatic, both primary and secondary, amines has been converted to the corresponding tertiary amines, including [N-13C]-labelled drugs, in good to excellent yields at mild conditions (see scheme; dppp=(1,3-bis(diphenylphosphino)propane)).
- Sorribes, Ivan,Junge, Kathrin,Beller, Matthias
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supporting information
p. 7879 - 7883
(2014/07/07)
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- End-to-end continuous flow synthesis and purification of diphenhydramine hydrochloride featuring atom economy, in-line separation, and flow of molten ammonium salts
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A continuous end-to-end synthesis and purification of diphenhydramine hydrochloride featuring atom economy and waste minimization is described. Combining a 1:1 molar ratio of the two starting material streams (chlorodiphenylmethane and N,N-dimethylaminoethanol) in the absence of additional solvent at high temperature gives the target compound directly as a molten salt (ionic liquid above 168 °C) in high yield. This represents the first example of continuous active pharmaceutical ingredient (API) production in this manner. Six of the twelve principles of green chemistry as defined by the American Chemical Society are achieved, most prominently waste minimization and atom economy.
- Snead, David R.,Jamison, Timothy F.
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p. 2822 - 2827
(2013/07/27)
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- Anti-inflammatory effects of two new methyl and morpholine derivatives of diphenhydramine on rats
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Diphenhydramines are one of the first-generation histamine H1-receptor antagonists of the ethanolamine class that demonstrate many pharmacological properties including anti-inflammatory effects. In this research, bromo (II) and two new tolyl derivatives of I, (Di [p-tolyl] [dimethylaminoethoxy] methane, III) and (Di [p-tolyl] [2-morpholinoethoxy] methane, IV) were synthesized. Their acute and chronic anti-inflammatory activities were evaluated with the formalin and histamine-induced rat paw edema. The vascular permeability in formalin and histamine-induced paw edema, in xylene-induced ear edema, and in peritonitis after acetic acid application into peritoneal cavity were also measured and compared to II. Cotton pellet-induced granuloma model was selected for inducing chronic inflammations in rats. The newly synthesized analogs of diphenhydramine seemed effective to decrease acute inflammations. It was concluded that the prominent anti-phlogistic effects of the new drugs could be related to its reduction vascular permeability mechanism(s) or to its antagonistic effects on H1 histamine receptors. Springer Science+Business Media, LLC 2011.
- Ahmadi, Abbas,Khalili, Mohsen,Hajikhani, Ramin,Safari, Narjes,Nahri-Niknafs, Babak
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p. 3532 - 3540
(2013/02/25)
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- Ruthenium-catalyzed /V-alkylation of amines and sulfonamides using borrowing hydrogen methodology
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The alkylation of amines by alcohols has been achieved using 0.5 mol percent [Ru(p-cymene)CI2]2 with the bidentate phosphines dppf or DPEphos as the catalyst. Primary amines have been converted into secondary amines, and secondary amines into tertiary amines, including the syntheses of Piribedil, Tripelennamine, and Chlorpheniramine. A/-Heterocyclization reactions of primary amines are reported, as well as alkylation reactions of primary sulfonamides. Secondary alcohols requiremore forcing conditions than primary alcohols but are still effective a lkylating agents in the presence of this catalyst.
- Hamid, M. Haniti S. A.,Allen, C. Liana,Lamb, Gareth W.,Maxwell, Aoife C.,Maytum, Hannah C.,et al.
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supporting information; experimental part
p. 1766 - 1774
(2009/07/25)
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- Hydroxy-oligocarboxylic esters: effects on nerve and use for cutaneous and mucocutaneous organs or sites
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A composition and method for producing a beneficial effect on a subject's nerve associated with at least one of a cosmetic condition, a dermatological indication and a dental indication and another condition. The composition comprises a hydroxy-oligocarboxylic ester and is formulated for topical administration of the product to a subject to produce the beneficial effect. The method includes topically applying to the subject in a region where the beneficial effect is desired a hydroxy-oligocarboxylic ester in an amount effective to produce the beneficial effect.
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