150-59-4Relevant academic research and scientific papers
Design and synthesis of alverine-based ionic liquids to improve drug water solubility
Fernández-Stefanuto,Esteiro,Santiago,Moreno,Palomar,Tojo
, p. 20428 - 20433 (2020)
Alverine [3-phenyl-N-(3-phenylpropyl)-N-ethylpropan-1-amine] is a widely known smooth muscle relaxant used to relieve cramps or spasms of the stomach and intestines. As a free base, alverine is a liquid practically insoluble in water while its commercialized form, alverine citrate, is a white solid that can form different crystalline forms. With the aim of increasing alverine water solubility while avoiding polymorphs, in this work, the design, total synthesis, and characterization of a series of new ionic liquids incorporating alverine as the cation were carried out. The selection of the most suitable anions for the active pharmaceutical ingredient-based ionic liquids (API-ILs) was performed calculating the ionic liquid solubility in water by using a priori the COSMO-RS computational tool. The computational analysis of the intermolecular interactions between water and the API-ILs allowed understanding the water solubility of these systems. All the new salts were found to be ionic liquids and their water solubility was shown to be significantly increased compared with the free drug alverine. The highest value was obtained for alverinium tosylate, with a value of 38.10 mg mL-1, 39937-fold higher than that of alverine. Compared to the commercialized drug alverine citrate, a slight increase in water-solubility was observed in all cases. This journal is
Alternative synthesis of alverine
Shakhmaev,Sunagatullina, A. Sh.,Zorin
, (2017)
An efficient synthesis of alverine via iron-catalyzed double cross-coupling of (2E)-3-chloro-N-[(2E)-3-chloroprop-2-en-1-yl]-N-ethylprop-2-en-1-amine with phenylmagnesium bromide is described.
Photocatalytic Water-Splitting Coupled with Alkanol Oxidation for Selective N-alkylation Reactions over Carbon Nitride
Xu, Yangsen,Zhang, Zhaofei,Qiu, Chuntian,Chen, Shaoqin,Ling, Xiang,Su, Chenliang
, p. 582 - 589 (2020/12/09)
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.
Pd/TiO2-Photocatalyzed Self-Condensation of Primary Amines to Afford Secondary Amines at Ambient Temperature
Wang, Lyu-Ming,Kobayashi, Kensuke,Arisawa, Mitsuhiro,Saito, Susumu,Naka, Hiroshi
, p. 341 - 344 (2018/12/11)
Symmetric secondary amines were synthesized by the self-condensation of primary amines over a palladium-loaded titanium dioxide (Pd/TiO2) photocatalyst. The reactions afforded a series of secondary amines in moderate to excellent isolated yields at ambient temperature (30 °C, in cyclopentyl methyl ether). Applicability for one-pot pharmaceutical synthesis was demonstrated by a photocatalytic reaction sequence of self-condensation of an amine followed by N-alkylation of the resulting secondary amine with an alcohol.
Method for reducing residues of N-ethyl-3-phenylpropylamine in alverine
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Paragraph 0055; 0060; 0061, (2018/11/03)
The invention relates to a method for reducing residues of N-ethyl-3-phenylpropylamine in alverine, and belongs to an impurity removal method of compounds. The method comprises the following steps: dissolving an intermediate alverine crude product containing impurity N-ethyl-3-phenylpropylamine into a water-insoluble organic solvent, extracting an organic layer by using an aqueous solution with appropriate pH and discarding a water layer; drying and filtering the organic layer, decompressing and evaporating the solvent to dryness. According to the method disclosed by the invention, a clear, simple and reliable solution to the residues of the N-ethyl-3-phenylpropylamine in the intermediate alverine is provided for the first time, so that the subsequently produced crude drug citric acid alverine has higher quality and the residue amount does not exceed 0.15 percent. The method has the advantages of simplicity, feasibility, low cost, few wastes and suitability for industrial popularization.
A new method for the preparation of alverine citrate
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Paragraph 0019; 0020, (2017/01/31)
The invention discloses a novel preparation method of alverine citrate, which comprises the following steps: reacting 3-phenylhalopropane and ethylamine hydrochloride used as initial raw materials in an alkaline system to generate diphenylpropyl ethylamine, and refining under the interaction between the organic layer and the citric acid to obtain the alverine citrate. The process route has the characteristics of accessible raw materials, fewer reaction steps, mild conditions, high yield and the like and is simple to operate, and thus, is an environment-friendly synthesis route which can easily implement industrialization.
Novel citric acid alverine crystal form and preparation method thereof
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Paragraph 0027; 0046, (2017/03/17)
The invention relates to a novel citric acid alverine crystal form, a preparation method thereof and a medicine composition using the crystal form as an active ingredient. The preparation method comprises the steps that phenylpropanol which is cheap and easy to obtain and serves as a start and is subjected to sulfoacid esterification and bromination to obtain 3-phenyl bromo propane; adding ethylamine hydrochloride in batches into excessive feed of the 3-phenyl bromo propane under the condition that organic base triethylamine and phase transfer catalyst exist to generate alverine free base in a 'one pot' mode; an organic layer is purified to be reacted with citric acid to produce crude citric acid alverine; the crude citric acid alverine is recrystallized through N-methyl pyrrolidone-water-DMF mixed solvent to obtain the novel crystal form B. Characteristic diffraction peaks are achieved at the positions of 4.18, 15.21, 20.53 and other positions of the value of 2 theta. The synthetic process route of the crystal form has the advantages that raw materials are easy to obtain, few reaction steps are needed, the condition is mild, operation is simple, and yield is high, and is environmentally friendly and easy to industrialize.
Benzimidazolin-2-ylidene N-heterocyclic carbene complexes of ruthenium as a simple catalyst for the N-alkylation of amines using alcohols and diols
Shan, Siah Pei,Xiaoke, Xie,Gnanaprakasam, Boopathy,Dang, Tuan Thanh,Ramalingam, Balamurugan,Huynh, Han Vinh,Seayad, Abdul Majeed
, p. 4434 - 4442 (2015/02/19)
Simple air and moisture stable ruthenium complexes 1-3 and 3a were synthesized from readily available benzannulated N-heterocyclic carbene ligands (bimy = benzimidazolin-2-ylidene). These complexes were found to be efficient catalysts for the alkylation of amines using alcohols as alkylating agents. Catalysts 1, 2 and 3a gave excellent yields of up to 99% for the alkylation of various amines using benzylic and aliphatic alcohols at 130 °C for 18 h under solventless conditions. Catalyst 3a bearing both phosphine and carbene ligands gave excellent yields of up to 98% for the synthesis of heterocyclic amines by double alkylation of primary amines using linear diols. The practical utility of these catalysts was demonstrated for the synthesis of pharmaceutically important amines in a more environmentally benign way under solventless conditions.
Construction of 3-arylpropylamines using Heck arylations. the total synthesis of cinacalcet hydrochloride, alverine, and tolpropamine
Prediger, Patrícia,Da Silva, Allan Ribeiro,Correia, Carlos Roque Duarte
, p. 3333 - 3341 (2014/05/06)
New synthetic routes toward the commercial drugs cinacalcet hydrochloride, alverine, and tolpropamine were developed using a Heck-Matsuda arylation as the key-step. Several reaction conditions were evaluated for the Heck-Matsuda reaction using allylamine derivatives and arenediazonium salts. For cinacalcet hydrochloride, N-formylamide provided the best result, furnishing the synthetic target in a very high overall yield (75% over five steps). For alverine, the best results were obtained using a double Heck-Matsuda strategy, providing alverine in an excellent overall yield (69%) from N-acetyl diallylamine in three steps. Tolpropamine was synthesized in a 46% yield over five steps using an efficient reductive Heck-Matsuda arylation between p-bromo-methylcinnamate with 3-chloro tolyldiazonium salt, generating the ,diaryl propionate that was converted to tolpropamine.
