181289-58-7Relevant articles and documents
Continuous-Flow Synthesis of Tramadol from Cyclohexanone
Monos, Timothy M.,Jaworski, Jonathan N.,Stephens, John C.,Jamison, Timothy F.
supporting information, p. 1888 - 1893 (2020/11/24)
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.
Catalytic Intramolecular Coupling of Ketoalkenes by Allylic C(sp3)?H Bond Cleavage: Synthesis of Five- and Six-Membered Carbocyclic Compounds
Mita, Tsuyoshi,Sato, Yoshihiro,Uchiyama, Masashi
, (2020/02/05)
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.).
Simultaneous chiral separation of tramadol and methadone in tablets, human urine, and plasma by capillary electrophoresis using maltodextrin as the chiral selector
Naghdi, Elahe,Fakhari, Ali Reza
, p. 1161 - 1168 (2018/09/06)
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.
Across-the-World Automated Optimization and Continuous-Flow Synthesis of Pharmaceutical Agents Operating Through a Cloud-Based Server
Fitzpatrick, Daniel E.,Maujean, Timothé,Evans, Amanda C.,Ley, Steven V.
supporting information, p. 15128 - 15132 (2018/10/31)
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.
Optimization of throughput in semipreparative chiral liquid chromatography using stacked injection
Taheri, Mohammadreza,Fotovati, Mohsen,Hosseini, Seyed-Kiumars,Ghassempour, Alireza
, p. 579 - 588 (2017/09/29)
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.
Biomimetic synthesis of Tramadol
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
, p. 14451 - 14453 (2015/09/28)
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.
Comparative performance evaluation and systematic screening of solvents in a range of Grignard reactions
Kadam, Asha,Nguyen, Mylinh,Kopach, Michael,Richardson, Paul,Gallou, Fabrice,Wan, Zhao-Kui,Zhang, Wei
, p. 1880 - 1888 (2013/09/24)
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.
COMPOSITIONS AND METHODS FOR OVERCOMING RESISTANCE TO TRAMADOL
-
Paragraph 0210, (2013/03/26)
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.
Simultaneous analysis of tramadol, O-desmethyltramadol, and N-desmethyltramadol enantiomers in rat plasma by high-performance liquid chromatography-tandem mass spectrometry: Application to pharmacokinetics
Godoy, Ana Leonor Pardo Campos,De Moraes, Natalia Valadares,Martinez, Edson Zangiacomi,Carvalho, Teresa Maria De Jesus Ponte,Marques, Maria Paula,Lanchote, Vera Lucia
body text, p. 287 - 293 (2012/01/05)
Tramadol (T) is available as a racemic mixture of (+)-trans-T and (-)-trans-T. The main metabolic pathways are O-demethylation and N-demethylation, producing trans-O-desmethyltramadol (M1) and trans-N-desmethyltramadol (M2) enantiomers, respectively. The analgesic effect of T is related to the opioid activity of (+)-trans-T and (+)-M1 and to the monoaminergic action of (+/-)-trans-T. This is the first study using tandem mass spectrometry as a detection system for the simultaneous analysis of trans-T, M1, and M2 enantiomers. The analytes were resolved on a ChiralpakA AD column using hexane:ethanol (95.5:4.5, v/v) plus 0.1% diethylamine as the mobile phase. The quantitation limits were 0.5 ng/ml for trans-T and M1 and 0.1 ng/ml for M2. The method developed and validated here was applied to a pharmacokinetic study in rats. Male Wistar rats (n = 6 at each time point) received a single oral dose of 20 mg/kg racemic trans-T. Blood samples were collected up to 12 h after drug administration. The kinetic disposition of trans-T and M2 was enantioselective (AUC(+)/(-) ratio = 4.16 and 6.36, respectively). The direction and extent of enantioselectivity in the pharmacokinetics of trans-T and M2 in rats were comparable to data previously reported for healthy volunteers, suggesting that rats are a suitable model for enantioselective studies of trans-T pharmacokinetics. Chirality, 2011.
Reaction of Grignard reagents with carbonyl compounds under continuous flow conditions
Riva,Gagliardi,Martinelli,Passarella,Vigo,Rencurosi
experimental part, p. 3242 - 3247 (2010/05/19)
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.
