- Continuous-Flow Synthesis of Tramadol from Cyclohexanone
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A multioperation, continuous-flow platform for the synthesis of tramadol, ranging from gram to decagram quantities, is described. The platform is segmented into two halves allowing for a single operator to modulate between preparation of the intermediate by Mannich addition or complete the fully concatenated synthesis. All purification operations are incorporated in-line for the Mannich reaction. 'Flash' reactivity between meta-methoxyphenyl magnesium bromide and the Mannich product was controlled with a static helical mixer and tested with a combination of flow and batch-based and factorial evaluations. These efforts culminated in a rapid production rate of tramadol (13.7 g°h -1) sustained over 56 reactor volumes. A comparison of process metrics including E-Factor, production rate, and space-time yield are used to contextualize the developed platform with respect to established engineering and synthetic methods for making tramadol.
- Monos, Timothy M.,Jaworski, Jonathan N.,Stephens, John C.,Jamison, Timothy F.
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p. 1888 - 1893
(2020/11/24)
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- Catalytic Intramolecular Coupling of Ketoalkenes by Allylic C(sp3)?H Bond Cleavage: Synthesis of Five- and Six-Membered Carbocyclic Compounds
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In the presence of a catalytic amount of cobalt(II) acetylacetonate/Xantphos in combination with trimethylaluminum, various ketoalkenes underwent an intramolecular cyclization reaction triggered by cleavage of the allylic C(sp3)?H bond, affording carbocyclic compounds with high regio- and diastereoselectivity. Mono-, bi-, and tricarbocyclic compounds were produced in good yields. One of the products thus obtained was derivatized into tramadol in four simple steps. Notably, these intramolecular cyclizations took place in the absence of a gem-disubstituent on the tethered carbon chain (without the Thorpe-Ingold effect). (Figure presented.).
- Mita, Tsuyoshi,Sato, Yoshihiro,Uchiyama, Masashi
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- Across-the-World Automated Optimization and Continuous-Flow Synthesis of Pharmaceutical Agents Operating Through a Cloud-Based Server
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The power of the Cloud has been harnessed for pharmaceutical compound production with remote servers based in Tokyo, Japan being left to autonomously find optimal synthesis conditions for three active pharmaceutical ingredients (APIs) in laboratories in Cambridge, UK. A researcher located in Los Angeles, USA controlled the entire process via an internet connection. The constituent synthetic steps for Tramadol, Lidocaine, and Bupropion were thus optimized with minimal intervention from operators within hours, yielding conditions satisfying customizable evaluation functions for all examples.
- Fitzpatrick, Daniel E.,Maujean, Timothé,Evans, Amanda C.,Ley, Steven V.
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supporting information
p. 15128 - 15132
(2018/10/31)
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- Simultaneous chiral separation of tramadol and methadone in tablets, human urine, and plasma by capillary electrophoresis using maltodextrin as the chiral selector
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The stereoselective analysis and separation of racemic drugs play an important role in pharmaceutical industry to eliminate the unwanted isomer and find the right therapeutic control for the patient. Present study suggests a maltodextrin-modified capillary electrophoresis method for a single‐run chiral separation of two closely similar opiate pain relief drugs: tramadol (TRA) and methadone (MET). The best separation method possible for the both enantiomers was achieved on an uncoated fused‐silica capillary at 25°C using 100 mM phosphate buffer (pH 8.0) containing 20% (w v?1) maltodextrin with dextrose equivalent of 4–7 and an applied voltage of 16 kV. Under optimal conditions, the baseline resolution of TRA and MET enantiomers was obtained in less than 12 minutes. The relative standard deviations (n = 3) of 20 μg mL?1 TRA and MET were 2.28% and 3.77%, respectively. The detection limits were found to be 2 μg mL?1 for TRA and 1.5 μg mL?1 for MET. This method was successfully applied to the measurement of drugs concentration in their tablets, urine, and plasma samples.
- Naghdi, Elahe,Fakhari, Ali Reza
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p. 1161 - 1168
(2018/09/06)
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- Optimization of throughput in semipreparative chiral liquid chromatography using stacked injection
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An interesting mode of chromatography for preparation of pure enantiomers from pure samples is the method of stacked injection as a pseudocontinuous procedure. Maximum throughput and minimal production costs can be achieved by the use of total chiral column length in this mode of chromatography. To maximize sample loading, often touching bands of the two enantiomers is automatically achieved. Conventional equations show direct correlation between touching-band loadability and the selectivity factor of two enantiomers. The important question for one who wants to obtain the highest throughput is “How to optimize different factors including selectivity, resolution, run time, and loading of the sample in order to save time without missing the touching-band resolution?” To answer this question, tramadol and propranolol were separated on cellulose 3,5-dimethyl phenyl carbamate, as two pure racemic mixtures with low and high solubilities in mobile phase, respectively. The mobile phase composition consisted of n-hexane solvent with alcohol modifier and diethylamine as the additive. A response surface methodology based on central composite design was used to optimize separation factors against the main responses. According to the stacked injection properties, two processes were investigated for maximizing throughput: one with a poorly soluble and another with a highly soluble racemic mixture. For each case, different optimization possibilities were inspected. It was revealed that resolution is a crucial response for separations of this kind. Peak area and run time are two critical parameters in optimization of stacked injection for binary mixtures which have low solubility in the mobile phase.
- Taheri, Mohammadreza,Fotovati, Mohsen,Hosseini, Seyed-Kiumars,Ghassempour, Alireza
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p. 579 - 588
(2017/09/29)
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- Biomimetic synthesis of Tramadol
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Tramadol has recently been isolated from the roots and bark of Nauclea latifolia. A plausible biosynthetic pathway has been proposed and the product-precursor relationship has been probed by 13C position-specific isotope analysis. By further exploring this pathway, we demonstrate that a key step of the proposed pathway can be achieved using mild conditions that mimic in vivo catalysis.
- Lecerf-Schmidt, Florine,Haudecoeur, Romain,Peres, Basile,Ferreira Queiroz, Marcos Mar?al,Marcourt, Laurence,Challal, Soura,Ferreira Queiroz, Emerson,Sotoing Taiwe, Germain,Lomberget, Thierry,Le Borgne, Marc,Wolfender, Jean-Luc,De Waard, Michel,Robins, Richard J.,Boumendjel, Ahcène
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supporting information
p. 14451 - 14453
(2015/09/28)
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- COMPOSITIONS AND METHODS FOR OVERCOMING RESISTANCE TO TRAMADOL
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There is disclosed a composition for oral administration of O-desmethyltramadol. There is further disclosed a method for treating disorders modulated by at least opiate receptor activity or monoamine activity, including acute and chronic pain, comprising administering a pharmaceutical formulation comprising O-desmethyltramadol. Compositions and methods are also provided that are effective for overcoming resistance to tramadol in patients.
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Paragraph 0210
(2013/03/26)
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- Comparative performance evaluation and systematic screening of solvents in a range of Grignard reactions
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The solvent effect on the Grignard reaction of benzyl, aryl and heteroaromatic substrates has been systematically evaluated based on reaction efficiency, ease of subsequent work-up, safety and greenness. 2-Methyltetrahydrofuran (2-MeTHF), which can be derived from renewable resources, had at least an equal if not a superior overall process most notably in suppressing the Wurtz coupling by-product from the benzyl Grignard reactions. It is therefore a recommended alternative solvent to Et2O and THF for the preparation of most Grignard reagents and their subsequent reactions.
- Kadam, Asha,Nguyen, Mylinh,Kopach, Michael,Richardson, Paul,Gallou, Fabrice,Wan, Zhao-Kui,Zhang, Wei
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p. 1880 - 1888
(2013/09/24)
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- Reaction of Grignard reagents with carbonyl compounds under continuous flow conditions
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This contribution details how a continuous flow reactor was used to react carbonyl compounds with Grignard reagents at room temperature in an efficient and safe manner. Flow rate, residence time and temperature were optimized for the preparation of a small collection of secondary and tertiary alcohols. Excellent yields and general applicability were observed using the set-up protocol. The procedure was also applied for the preparation of Tramadol, an analgesic drug belonging to the opioid group. The developed conditions allowed the selective addition of Grignard reagents to aldehydes and ketones in the presence of a nitrile function.
- Riva,Gagliardi,Martinelli,Passarella,Vigo,Rencurosi
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experimental part
p. 3242 - 3247
(2010/05/19)
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- SUBSTITUTED CYCLOHEXANOLS
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Disclosed herein are substituted cyclohexanol opioid receptor modulators and/or neurotransmitter reuptake modulators of Formula I or Formula II, process of preparation thereof, pharmaceutical compositions thereof, and methods of use thereof.
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Page/Page column 33-34
(2009/02/11)
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- Immunoassay for tramadol and its major metabolites
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The invention provides a method and kit for detecting and determining tramadol and its major metabolites N-demethyltramadol and O-demethyltramadol using novel conjugates, immunogens and antibodies derived from N-derivatised and O-derivatised tramadol.
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- Application of microreactor technology in process development
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The microreactor technology is an efficient tool for kilogram-scale syntheses in continuous mode and is particularly effective for hazardous reactions that do not allow scale-up in conventional reactors. Applications to several classes of reactions including highly exothermic reactions, high-temperature reactions, reactions with unstable intermediates, and reactions involving hazardous reagents are described herein.
- Zhang, Xini,Stefanick, Stephen,Villani, Frank J.
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p. 455 - 460
(2013/09/05)
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- METHOD FOR THE PRODUCTION OF 2-[(DIMETHYLAMINO)METHYL]-1-(3-METHOXYPHENYL)CYCLOHEXANOL
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The invention relates to a method for the production of 2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol with high stereoselectivity and in high yield.
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Page/Page column 1; 6; 8-9
(2010/02/06)
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- Combination of selected opioids with muscarine antagonists for treating urinary incontinence
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Active compound combinations of compounds of group A, particularly opioids, and compounds of group B, particularly anti-muscarine agents and other substances suitable for treatment of an increased urge to urinate or urinary incontinence. Related pharmaceutical formulations and methods of treatment of an increased urge to urinate or urinary incontinence are also provided.
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- Tramadol analogs and uses thereof
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Compounds of formula I are effective in treating disorders modulated by opiate receptor activity and/or monoamine activity. In formula I, R1 is selected from alkyl, aryl, alkylaryl, substituted alkyl, substituted aryl, and substituted alkylaryl; R2 is selected from hydrogen, hydroxy, cyano, haloalkyl, glycosyl, SO2R5, and OR5; R3 and R4 are independently selected from hydrogen and lower alkyl, or R3 and R4 taken together with nitrogen form a five- or six-membered heterocyclic or substituted heterocyclic ring; and R5 is selected from alkyl, aryl, alkylaryl, substituted alkyl, substituted aryl, and substituted alkylaryl.
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- Development of highly efficient resolutions of racemic tramadol using mandelic acid
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Two methods for the resolution of tramadol are described. One uses the active pharmaceutical ingredient (API), tramadol hydrochloride as input material. The other utilises the crude free base obtained from the Grignard reaction on tramadol Mannich base. B
- Evans, Graham R.,Fernandez, Paloma Diaz,Henshilwood, James A.,Lloyd, Steve,Nicklin, Chris
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p. 729 - 737
(2013/09/06)
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- Synthesis and purification of (r*,r*)-2-[ (dimethylamino) methyl]-1-(3-methoxyphenyl) cyclohexanol hydrochloride
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(R*,R*)-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol (Tramadol) is synthesized in a Grignard reaction in the presence of an additive resulting in a higher trans:cis ratio of product than is obtained in the absence of the additive. The Grignard reaction between 3 bromoanisole and the appropriate Mannich base in the presence of an amine or ether additive gives the amine product in an improved trans/cis ratio. The base is converted to its hydrochloride and recrystallized from a low molecular weight nitrile such as acetonitrile until a greater than 98% trans/cis ratio is obtained. Recrystallization from isopropanol gives (R*,R*)2-[(dimethylamino)methyl]-1-(3-metboxyphenyl)cyclohexanol hydrochloride free of the nitrile solvent. A hydrochloride of Tramadol can be synthesized without increasing a ratio of trans:cis by including a step in which HCl is added to Tramadol base in the presence of toluene.
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- Process
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A process for preparing a substantially single enantiomer of tramadol, or a pharmaceutically-acceptable salt thereof, proceeds by means of a classical salt resolution using a substantially single enantiomer of O,O-di-p-toluoyltartaric acid as a resolving agent.
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- Application of Grignard reagents to the synthesis of tertiary methylamines via resin-bound oxyiminium ions
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The solid-phase synthesis of tertiary methylamines via the nucleophilic displacement of benzotriazole Mannich adducts with Grignard reagents using a hydroxylamine linker is described. The chemistry is exemplified by the synthesis of the MAO inhibitor α-methylpargyline. Also described is the synthesis of the analgesic Tramadol by an alternative one-pot solid-phase Mannich reaction. (C) 2000 Elsevier Science Ltd.
- Blaney,Grigg,Rankovic,Thoroughgood
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p. 6639 - 6642
(2007/10/03)
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- Method of separating the racemate of tramadol
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A method of separating the racemate of tramadol is disclosed.
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- Method of preparing the enantiomers of O-dimethyltramadol
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A method of preparing the enantiomers of O-demethyltramadol and the use of the enantiomers as pain-killing drugs are described.
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- Process for the purification of (RR-SS)-2-dimethyl-aminomethyl-1-(3-methoxyphenyl)cyclohexanol and its salts
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The invention provides a process for the purification and isolation of (RR,SS)-2-dimethylaminomethyl-1-(3-methoxyphenyl)cyclohexanol from mixtures also containing the (RS,SR) isomer comprising reacting the above mixture in a solvent at elevated temperature under acidic conditions, whereby the (RS,SR) isomer is selectively converted to the (RR,SS) isomer, 1-(3-methoxyphenyl)-2-dimethylaminomethylcyclohex-6-ene, 1-(3-methoxyphenyl)-2-dimethyl-aminomethylcyclohex-1-ene or a mixture thereof, selectively precipitating the desired (RR,SS) isomer as an amine acid salt, and recrystallizing the purified product.
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- Process for the purification of (RR-SS)-2-dimethyl-aminomethyl-1-(3-methoxyphenyl)cyclohexanol and its salts
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The invention provides a process for the purification and isolation of (RR,SS)-2-dimethylaminomethyl-1-(3-methoxyphenyl)cyclohexanol from mixtures also containing the (RS,SR) isomer comprising reacting the above mixture in a solvent at elevated temperature under acidic conditions, whereby the (RS,SR) isomer is selectively converted to the (RR,SS) isomer, 1-(3-methoxyphenyl)-2-dimethylaminomethylcyclohex-6-ene, 1-(3-methoxyphenyl)-2-dimethyl-aminomethylcyclohex-1-ene or a mixture thereof, selectively precipitating the desired (RR,SS) isomer as an amine acid salt, and recrystallizing the purified product.
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