- Quantitative structure-activity relationships in drug metabolism and disposition: Pharmacokinetics of N-substituted amphetamines in humans
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Pharmacokinetic data of 15 N-alkyl-substituted amphetamines in humans have been the object of a retrospective quantitative structure-activity relationship study. The urinary excretion of amphetamines was shown to decrease with increasing lipophilicity; the correlation equations revealed that, for identical lipophilicities, tertiary amines are excreted faster than secondary amines, which are secreted faster than primary amines. The apparent n-heptane-pH 7.4 buffer partition coefficient correlates better with urinary excretion than does the true n-octanol-water partition coefficient, probably because it includes a pKa term that accounts for the fraction of the drug present in the tubules as nonionic species. The N-dealkylation rate increases with increasing lipophilicity of the substrates (enhanced enzyme affinity) but decreases with increasing bulk of the N-substituent that is split off (steric hindrance of initial C(α)-hydroxylation.
- Testa,Salvesen
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- Correlation between the6Li,15N coupling constant and the coordination number at lithium
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The 6Li,15N coupling constants of lithium amide dimers and their mixed complexes with n-butyllithium, formed from five different chiral amines derived from (S)-[15N]phenylalanine, were determined in diethyl ether (Et2O), tetrahydrofuran (THF) and toluene. Results of NMR spectroscopy studies of these complexes show a clear difference in 6Li, 15N coupling constants between di-, tri- and tetracoordinated lithium atoms. The lithium amide dimers with a chelating ether group exhibit 6Li,15N coupling constants of ~3.8 and ~5.5 Hz for the tetracoordinated and tricoordinated lithium atoms, respectively. The lithium amide dimers with a chelating thioether group show distinctly larger 6Li,15N coupling constants of ~4.4 Hz for the tetracoordinated lithium atoms, and the tricoordinated lithium atoms have smaller 6Li, 15N coupling constants, ~4.9 Hz, than their ether analogues. In diethyl ether and tetrahydrofuran, mixed dimeric complexes between the lithium amides and n-butyllithium are formed. The tetracoordinated lithium atoms of these complexes have 6Li, 15N coupling constants of ~4.0 Hz, and the 6Li, 15N coupling constants of the tricoordinated lithium atoms differ somewhat, depending on whether the chelating group is an ether or a thioether; ~5.1 and ~4.6 Hz, respectively. In toluene, mixed trimeric complexes are formed from two lithium amide moieties and one n-butyl-lithium. In these trimers, two lithium atoms are tricoordinated with 6Li,15N coupling constants of ~4.6 Hz and one lithium is dicoordinated with 6Li,15N coupling constants of ~6.5 Hz.
- Granander, Johan,Sott, Richard,Hilmersson, Goeran
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- δ13C and δ13H isotope ratios in amphetamine synthesized from benzaldehyde and nitroethane
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Previous work in these laboratories and by Butzenlechner et al. and Culp et al. has demonstrated that the δ2H isotope value of industrial benzaldehyde produced by the catalytic oxidation of toluene is profoundly positive, usually in the range +300% to +500%. Synthetic routes leading to amphetamine, methylamphetamine or their precursors and commencing with such benzaldehyde may be expected to exhibit unusually positive δ2H values. Results are presented for δ13C and δ2H isotope values of 1-phenyl-2-nitropropene synthesized from an industrial source of benzaldehyde, having a positive δ2H isotope value, by a Knoevenagel condensation with nitroethane. Results are also presented for δ13C and δ2H isotope values for amphetamine prepared from the resulting 1-phenyl-2-nitropropene. The values obtained were compared with δ13C and δ2H isotope values obtained for an amphetamine sample prepared using a synthetic route that did not involve benzaldehyde. Finally, results are presented for samples of benzaldehyde, 1-phenyl-2-nitropropene and amphetamine that had been seized at a clandestine amphetamine laboratory.
- Collins, Michael,Salouros, Helen,Cawley, Adam T.,Robertson, James,Heagney, Aaron C.,Arenas-Queralt, Andrea
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- An ammonia equivalent for the dimethyltitanocene-catalyzed intermolecular hydroamination of alkynes
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(Equation presented) Commercially available α-aminodiphenylmethane 1 (benzhydrylamine) serves as a convenient ammonia equivalent in the dimethyltitanocene-catalyzed intermolecular hydroamination of alkynes. The primary formed imines can be hydrogenated and cleaved directly to the corresponding primary amines by catalytic hydrogenation using Pd/C as catalyst.
- Haak, Edgar,Siebeneicher, Holger,Doye, Sven
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- Reduction of amphetamine hydroxylamine and other aliphatic hydroxylamines by benzamidoxime reductase and human liver microsomes
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For the reduction of N-hydroxylated derivatives of strongly basic functional groups, such as amidines, guanidines, and aminohydrazones, an oxygen-insensitive liver microsomal system, the benzamidoxime reductase, has been described. To reconstitute the complete activity of the benzamidoxime reductase, the system required cytochrome b5, NADH-cytochrome b5-reductase, and the benzamidoxime reductase, a cytochrome P450 enzyme, which has been purified to homogeneity from pig liver. It was not known if this enzyme system was also capable of reducing aliphatic hydroxylamines. The N-hydroxylation of aliphatic amines is a well-known metabolic process. It was of interest to study the possibility of benzamidoxime reductase reducing N-hydroxylated metabolites of aliphatic amines back to the parent compound. Overall, N-hydroxylation and reduction would constitute a futile metabolic cycle. As examples of medicinally relevant compounds, the hydroxylamines ofmethamphetamine, amphetamine, and N-methylamine as model compounds were investigated. Formation of methamphetamine and amphetamine was analyzed by newly developed HPLC methods. All three hydroxylamines were easily reduced by benzamidoxime reductase to their parent amines with reduction rates of 220.6 nmol min-1 (mg of protein)-1 for methamphetamine, 5.25 nmol min-1 (mg of protein)-1 for amphetamine, and 153 nmol min-1 (mg of protein)-1 for N-methylhydroxylamine. Administration of synthetic hydroxylamines of amphetamine and methamphetamine to primary rat neuronal cultures produced frank cell toxicity. Compared with amphetamine or the oxime of amphetamine, the hydroxylamines were significantly more toxic to primary neuronal cells. The benzamidoxime reductase is therefore involved in the detoxication of these reactive hydroxylamines.
- Clement,Behrens,Moller,Cashman
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- ASPARAGINE DERIVATIVES AND METHODS OF USE THEREOF
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The present invention relates to compounds of formulas (A) and (I), pharmaceutically acceptable salts thereof, and solvates of any of them, pharmaceutical compositions comprising them, methods of preparation thereof, intermediate compounds useful for the preparation thereof, and methods of treatment or prophylaxis of diseases, in particular cancer, such as colorectal cancer, using these. (A) (I)
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- Markovnikov Wacker-Tsuji Oxidation of Allyl(hetero)arenes and Application in a One-Pot Photo-Metal-Biocatalytic Approach to Enantioenriched Amines and Alcohols
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The Wacker-Tsuji aerobic oxidation of various allyl(hetero)arenes under photocatalytic conditions to form the corresponding methyl ketones is presented. By using a palladium complex [PdCl2(MeCN)2] and the photosensitizer [Acr-Mes]ClO4 in aqueous medium and at room temperature, and by simple irradiation with blue led light, the desired carbonyl compounds were synthesized with high conversions (>80%) and excellent selectivities (>90%). The key process was the transient formation of Pd nanoparticles that can activate oxygen, thus recycling the Pd(II) species necessary in the Wacker oxidative reaction. While light irradiation was strictly mandatory, the addition of the photocatalyst improved the reaction selectivity, due to the formation of the starting allyl(hetero)arene from some of the obtained by-products, thus entering back in the Wacker-Tsuji catalytic cycle. Once optimized, the oxidation reaction was combined in a one-pot two-step sequential protocol with an enzymatic transformation. Depending on the biocatalyst employed, i. e. an amine transaminase or an alcohol dehydrogenase, the corresponding (R)- and (S)-1-arylpropan-2-amines or 1-arylpropan-2-ols, respectively, could be synthesized in most cases with high yields (>70%) and in enantiopure form. Finally, an application of this photo-metal-biocatalytic strategy has been demonstrated in order to get access in a straightforward manner to selegiline, an anti-Parkinson drug. (Figure presented.).
- Albarrán-Velo, Jesús,Gotor-Fernández, Vicente,Lavandera, Iván
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supporting information
p. 4096 - 4108
(2021/08/19)
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- Direct Access to Primary Amines from Alkenes by Selective Metal-Free Hydroamination
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Direct and selective synthesis of primary amines from easily available precursors is attractive yet challenging. Herein, we report the rapid synthesis of primary amines from alkenes via metal-free regioselective hydroamination at room temperature. Ammonium carbonate was used as ammonia surrogate for the first time, allowing for efficient conversion of terminal and internal alkenes into linear, α-branched, and α-tertiary primary amines under mild conditions. This method provides a straightforward and powerful approach to a wide spectrum of advanced, highly functionalized primary amines which are of particular interest in pharmaceutical chemistry and other areas.
- Du, Yi-Dan,Chen, Bi-Hong,Shu, Wei
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supporting information
p. 9875 - 9880
(2021/03/29)
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- Transaminase-mediated synthesis of enantiopure drug-like 1-(3′,4′-disubstituted phenyl)propan-2-amines
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Transaminases (TAs) offer an environmentally and economically attractive method for the direct synthesis of pharmaceutically relevant disubstituted 1-phenylpropan-2-amine derivatives starting from prochiral ketones. In this work, we report the application of immobilised whole-cell biocatalysts with (R)-transaminase activity for the synthesis of novel disubstituted 1-phenylpropan-2-amines. After optimisation of the asymmetric synthesis, the (R)-enantiomers could be produced with 88-89% conversion and >99% ee, while the (S)-enantiomers could be selectively obtained as the unreacted fraction of the corresponding racemic amines in kinetic resolution with >48% conversion and >95% ee. This journal is
- Lakó, ágnes,Mendon?a, Ricardo,Molnár, Zsófia,Poppe, László
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p. 40894 - 40903
(2020/11/23)
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- Determination of the chiral status of different novel psychoactive substance classes by capillary electrophoresis and β-cyclodextrin derivatives
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Besides the abuse of well-known illicit drugs, consumers discovered new synthetic compounds with similar effects but minor alterations in their chemical structure. Originally, these so-called novel psychoactive substances (NPS) have been created to circumvent law of prosecution because of illicit drug abuse. During the past decade, such compounds came up in generations, the most popular compound was a synthetic cathinone derivative named mephedrone. Cathinones are structurally related to amphetamines; to date, more than 120 completely new derivatives have been synthesized and are traded via the Internet. Cathinones possess a chiral center; however, only little is known about the pharmacology of their enantiomers. However, NPS comprise further chiral compound classes such as amphetamine derivatives, ketamines, 2-(aminopropyl)benzofurans, and phenidines. In continuation of our project, a cheap and easy-to-perform chiral capillary zone electrophoresis method for enantioseparation of cathinones presented previously was extended to the aforementioned compound classes. Enantioresolution was achieved by simply adding native β-cyclodextrin, acetyl-β-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, or carboxymethyl-β-cyclodextrin as chiral selector additives to the background electrolyte. Fifty-one chiral NPS served as analytes mainly purchased from online vendors via the Internet. Using 10 mM of the aforementioned β-cyclodextrins in a 10 mM sodium phosphate buffer (pH 2.5), overall, 50 of 51 NPS were resolved. However, chiral separation ability of the selectors differed depending on the analyte. Additionally, simultaneous enantioseparations, the determination of enantiomeric migration orders of selected analytes, and a repeatability study were performed successfully. It was proven that all separated NPS were traded as racemic mixtures.
- H?gele, Johannes S.,Hubner, Eva-Maria,Schmid, Martin G.
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p. 1191 - 1207
(2020/07/21)
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- ENVIRONMENTALLY-FRIENDLY HYDROAZIDATION OF OLEFINS
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The present invention provides processes for the synthesis of organic azides, intermediates for the production thereof, and compositions related thereto.
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Page/Page column 63; 71-72
(2020/01/24)
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- APPLICATION FOR LETTERS PATENT
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This is invention is related to processes for synthesis of levoamphetamine derivatives and novel intermediates thereby, and processes for using the same.
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Paragraph 239-242
(2020/09/20)
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- Stereoselective Synthesis of 1-Arylpropan-2-amines from Allylbenzenes through a Wacker-Tsuji Oxidation-Biotransamination Sequential Process
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Herein, a sequential and selective chemoenzymatic approach is described involving the metal-catalysed Wacker-Tsuji oxidation of allylbenzenes followed by the amine transaminase-catalysed biotransamination of the resulting 1-arylpropan-2-ones. Thus, a series of nine optically active 1-arylpropan-2-amines were obtained with good to very high conversions (74–92%) and excellent selectivities (>99% enantiomeric excess) in aqueous medium. The Wacker-Tsuji reaction has been exhaustively optimised searching for compatible conditions with the biotransamination experiments, using palladium(II) complexes as catalysts and iron(III) salts as terminal oxidants in aqueous media. The compatibility of palladium/iron systems for the chemical oxidation with commercially available and made in house amine transaminases was analysed, finding ideal conditions for the development of a general and stereoselective cascade sequence. Depending on the selectivity displayed by selected amine transaminase, it was possible to produce both 1-arylpropan-2-amines enantiomers under mild reaction conditions, compounds that present therapeutic properties or can be employed as synthetic intermediates of chiral drugs from the amphetamine family. (Figure presented.).
- González-Martínez, Daniel,Gotor, Vicente,Gotor-Fernández, Vicente
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p. 2582 - 2593
(2019/05/15)
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- Efficient synthesis of enantiopure amines from alcohols using resting: E. coli cells and ammonia
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α-Chiral amines are pivotal building blocks for chemical manufacturing. Stereoselective amination of alcohols is receiving increased interest due to its higher atom-efficiency and overall improved environmental footprint compared with other chemocatalytic and biocatalytic methods. We previously developed a hydrogen-borrowing amination by combining an alcohol dehydrogenase (ADH) with an amine dehydrogenase (AmDH) in vitro. Herein, we implemented the ADH-AmDH bioamination in resting Escherichia coli cells for the first time. Different genetic constructs were created and tested in order to obtain balanced expression levels of the dehydrogenase enzymes in E. coli. Using the optimized constructs, the influence of several parameters towards the productivity of the system were investigated such as the intracellular NAD+/NADH redox balance, the cell loading, the survival rate of recombinant E. coli cells, the possible toxicity of the components of the reaction at different concentrations and the influence of different substrates and cosolvents. In particular, the cofactor redox-balance for the bioamination was maintained by the addition of moderate and precise amounts of glucose. Higher concentrations of certain amine products resulted in toxicity and cell death, which could be alleviated by the addition of a co-solvent. Notably, amine formation was consistent using several independently grown E. coli batches. The optimized E. coli/ADH-AmDH strains produced enantiopure amines from the alcohols with up to 80% conversion and a molar productivity up to 15 mM. Practical applicability was demonstrated in a gram-scale biotransformation. In summary, the present E. coli-ADH-AmDH system represents an important advancement towards the development of 'green', efficient and selective biocatalytic processes for the amination of alcohols.
- Houwman, Joseline A.,Knaus, Tanja,Costa, Magda,Mutti, Francesco G.
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supporting information
p. 3846 - 3857
(2019/07/31)
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- One-Pot Transformation of Ketoximes into Optically Active Alcohols and Amines by Sequential Action of Laccases and Ketoreductases or ω-Transaminases
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An enzymatic one-pot process for asymmetric transformation of prochiral ketoximes into alcohols or amines was developed by sequential coupling of a laccase-catalyzed deoximation either with a ketone reduction (ketoreductase, KRED) or bioamination (ω-transaminase, ω-TA) in aqueous medium. An accurate selection of biocatalysts provided the corresponding products in excellent enantiomeric excesses and overall conversions ranging from 83 to >99 % for alcohols and 70 to >99 % for amines. Likewise, the employment of exclusively 1 % (w/w) of Cremophor, a polyethoxylated castor oil, as co-solvent enabled to reach concentrations up to 100 mM in the chiral alcohols cascade.
- Correia Cordeiro, Raquel S.,Ríos-Lombardía, Nicolás,Morís, Francisco,Kourist, Robert,González-Sabín, Javier
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p. 1272 - 1277
(2019/01/24)
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- Amine Transaminase from Exophiala Xenobiotica - Crystal Structure and Engineering of a Fold IV Transaminase that Naturally Converts Biaryl Ketones
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Amine transaminases are frequently used for the production of chiral amines starting from prochiral ketones. These amines can be applied as active pharmaceutical ingredients or drug precursors. However, there are still limitations to the use of amine transaminases when it comes to bulky ketone substrates, such as biaryl ketones. Using data mining, an (R)-selective amine transaminase from Exophiala xenobiotica was identified which naturally converts biaryl ketone substrates to the corresponding amines with up to 85% conversion and excellent enantioselectivity (>99% ee). Its protein crystal structure was obtained with a resolution of 1.52 ?, which enabled us to explain this interesting substrate acceptance. Structure-guided protein engineering resulted in a quintuple variant with increased stability. Moreover, the amino acid exchange T273S increased the activity and broadened the substrate scope, enabling conversions of various biaryl ketones with up to >99%. A preparative biotransformation of 1-(4-(pyridin-3-yl)phenyl)ethenone at 75 mM (15 g/L) resulted in 96% of isolated yield of the respective amine.
- Telzerow, Aline,Paris, Juraj,H?kansson, Maria,González-Sabín, Javier,Ríos-Lombardía, Nicolás,Schürmann, Martin,Gr?ger, Harald,Morís, Francisco,Kourist, Robert,Schwab, Helmut,Steiner, Kerstin
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p. 1140 - 1148
(2019/01/21)
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- Enantiomeric separation of Novel Psychoactive Substances by capillary electrophoresis using (+)-18-crown-6-tetracarboxylic acid as chiral selector
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In the recent years, hundreds of Novel Psychoactive Substances (NPS) have entered both the European and the global drug market. These drugs, which are mainly used for recreational matters, have caused serious social problems. Every year, the spectrum of these misused drugs is enlarged by new derivatives, which are produced by modifications of basic structures of already well-known substances. Additionally, a lot of them possess a stereogenic center which leads to 2 enantiomeric forms. The fact that the pharmacological effects and potencies of the enantiomers of these chiral NPS may differ can be assumed from a broad spectrum of active pharmaceutical ingredients. For this reason, analytical method development regarding enantiomeric separation for these classes of substances is of great pharmaceutical and medical interest. The aim of this work was to create an easy-to-prepare chiral capillary electrophoresis method for the enantioseparation of NPS which contains a primary amino group by means of (+)-18-crown-6-tetracarboxylic acid as chiral selector. Novel Psychoactive Substances were purchased at various Internet stores or represent samples seized by Austrian police. The effects of selector concentration, the electrolyte composition, and the addition of organic modifiers to the background electrolyte on enantioseparation were investigated. Under optimized conditions, the use of 20-mM (+)-18-crown-6-tetracarboxylic acid, 10-mM Tris, and 30-mM citric acid buffer at pH 2.10 turned out to be effective. Fifteen of 24 tested NPS were resolved in their enantiomers within 15?minutes. It was found that all NPS were traded as racemic mixtures.
- H?gele, Johannes S.,Schmid, Martin G.
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p. 1019 - 1026
(2018/07/29)
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- Evaluation of the Edman degradation product of vancomycin bonded to core-shell particles as a new HPLC chiral stationary phase
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A modified macrocyclic glycopeptide-based chiral stationary phase (CSP), prepared via Edman degradation of vancomycin, was evaluated as a chiral selector for the first time. Its applicability was compared with other macrocyclic glycopeptide-based CSPs: TeicoShell and VancoShell. In addition, another modified macrocyclic glycopeptide-based CSP, NicoShell, was further examined. Initial evaluation was focused on the complementary behavior with these glycopeptides. A screening procedure was used based on previous work for the enantiomeric separation of 50 chiral compounds including amino acids, pesticides, stimulants, and a variety of pharmaceuticals. Fast and efficient chiral separations resulted by using superficially porous (core-shell) particle supports. Overall, the vancomycin Edman degradation product (EDP) resembled TeicoShell with high enantioselectivity for acidic compounds in the polar ionic mode. The simultaneous enantiomeric separation of 5 racemic profens using liquid chromatography-mass spectrometry with EDP was performed in approximately 3?minutes. Other highlights include simultaneous liquid chromatography separations of rac-amphetamine and rac-methamphetamine with VancoShell, rac-pseudoephedrine and rac-ephedrine with NicoShell, and rac-dichlorprop and rac-haloxyfop with TeicoShell.
- Hellinghausen, Garrett,Lopez, Diego A.,Lee, Jauh T.,Wang, Yadi,Weatherly, Choyce A.,Portillo, Abiud E.,Berthod, Alain,Armstrong, Daniel W.
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p. 1067 - 1078
(2018/08/01)
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- AMPHETAMINE CONTROLLED RELEASE, PRODRUG, AND ABUSE-DETERRENT DOSAGE FORMS
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The invention also relates to pharmaceutical compositions comprising highly pure amphetamine and amphetamine-class compounds resulting from the synthesis of chiral and racemic amphetamine derivatives by stereospecific, regioselective cuprate addition reaction with aziridine phosphoramidate compounds, and to methods of manufacturing, delivering, and using the amphetamine compounds resulting from the synthesis of chiral and racemic amphetamine derivatives by stereospecific, regioselective cuprate addition reaction with aziridine phosphoramidate compounds.
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Paragraph 0397; 0398
(2018/09/16)
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- Ligand-Enabled meta-Selective C-H Arylation of Nosyl-Protected Phenethylamines, Benzylamines, and 2-Aryl Anilines
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A Pd-catalyzed, meta-selective C-H arylation of nosyl-protected phenethylamines and benzylamines is disclosed using a combination of norbornene and pyridine-based ligands. Subjecting nosyl protected 2-aryl anilines to this protocol led to meta-C - H arylation at the remote aryl ring. A diverse range of aryl iodides are tolerated in this reaction, along with select heteroaryl iodides. Select aryl bromides bearing ortho-coordinating groups can also be utilized as effective coupling partners in this reaction. The use of pyridine ligands has allowed the palladium loading to be reduced to 2.5 mol %. Furthermore, a catalytic amount of 2-norbomene (20 mol %) to mediate this meta-C - H activation process is demonstrated for the first time. Utilization of a common protecting group as the directing group for meta-C-H activation of amines is an important feature of this reaction in terms of practical applications.
- Ding, Qiuping,Ye, Shengqing,Cheng, Guolin,Wang, Peng,Farmer, Marcus E.,Yu, Jin-Quan
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supporting information
p. 417 - 425
(2017/05/16)
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- AMPHETAMINE CONTROLLED RELEASE, PRODRUG, AND ABUSE DETERRENT DOSAGE FORMS
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The invention also relates to pharmaceutical compositions comprising highly pure amphetamine and amphetamine-class compounds resulting from the synthesis of chiral and racemic amphetamine derivatives by stereospecific, regioselective cuprate addition reaction with aziridine phosphoramidate compounds, and to methods of manufacturing, delivering, and using the amphetamine compounds resulting from the synthesis of chiral and racemic amphetamine derivatives by stereospecific, regioselective cuprate addition reaction with aziridine phosphoramidate compounds.
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- Hybrid Organo- and Biocatalytic Process for the Asymmetric Transformation of Alcohols into Amines in Aqueous Medium
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A hybrid organo- and biocatalytic system for the asymmetric conversion of racemic alcohols into amines was developed. Combining an organocatalyst, AZADO, an oxidant, NaOCl, and an enzyme, ω-transaminase, we implemented a one-pot oxidation-transamination sequential process in aqueous medium. The method showed broad substrate scope and was successfully applied to conventional secondary alcohols and sterically hindered β-substituted cycloalkanols, where a highly stereoselective dynamic asymmetric bioamination enabled us to set up both contiguous stereocenters with very high enantio- and diastereomeric ratio (>90% yield, >99% ee, and up to 49:1 dr).
- Liardo, Elisa,Ríos-Lombardía, Nicolás,Morís, Francisco,Rebolledo, Francisca,González-Sabín, Javier
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p. 4768 - 4774
(2017/07/24)
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- MOF-derived cobalt nanoparticles catalyze a general synthesis of amines
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The development of base metal catalysts for the synthesis of pharmaceutically relevant compounds remains an important goal of chemical research. Here, we report that cobalt nanoparticles encapsulated by a graphitic shell are broadly effective reductive amination catalysts. Their convenient and practical preparation entailed template assembly of cobaltdiamine- dicarboxylic acid metal organic frameworks on carbon and subsequent pyrolysis under inert atmosphere.The resulting stable and reusable catalysts were active for synthesis of primary, secondary, tertiary, and N-methylamines (more than 140 examples).The reaction couples easily accessible carbonyl compounds (aldehydes and ketones) with ammonia, amines, or nitro compounds, and molecular hydrogen under industrially viable and scalable conditions, offering cost-effective access to numerous amines, amino acid derivatives, and more complex drug targets.
- Jagadeesh, Rajenahally V.,Murugesan, Kathiravan,Alshammari, Ahmad S.,Neumann, Helfried,Pohl, Marga-Martina,Radnik, J?rg,Beller, Matthias
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p. 326 - 332
(2017/09/28)
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- In vitro biocatalytic pathway design: Orthogonal network for the quantitative and stereospecific amination of alcohols
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The direct and efficient conversion of alcohols into amines is a pivotal transformation in chemistry. Here, we present an artificial, oxidation-reduction, biocatalytic network that employs five enzymes (alcohol dehydrogenase, NADP-oxidase, catalase, amine dehydrogenase and formate dehydrogenase) in two concurrent and orthogonal cycles. The NADP-dependent oxidative cycle converts a diverse range of aromatic and aliphatic alcohol substrates to the carbonyl compound intermediates, whereas the NAD-dependent reductive aminating cycle generates the related amine products with >99% enantiomeric excess (R) and up to >99% conversion. The elevated conversions stem from the favorable thermodynamic equilibrium (K′eq = 1.88 × 1042 and 1.48 × 1041 for the amination of primary and secondary alcohols, respectively). This biocatalytic network possesses elevated atom efficiency, since the reaction buffer (ammonium formate) is both the aminating agent and the source of reducing equivalents. Additionally, only dioxygen is needed, whereas water and carbonate are the by-products. For the oxidative step, we have employed three variants of the NADP-dependent alcohol dehydrogenase from Thermoanaerobacter ethanolicus and we have elucidated the origin of the stereoselective properties of these variants with the aid of in silico computational models.
- Knaus, Tanja,Cariati, Luca,Masman, Marcelo F,Mutti, Francesco G.
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p. 8313 - 8325
(2017/10/19)
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- Coupled Immobilized Amine Dehydrogenase and Glucose Dehydrogenase for Asymmetric Synthesis of Amines by Reductive Amination with Cofactor Recycling
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The amine dehydrogenase (AmDH) engineered from the phenylalanine dehydrogenase of Rhodococcus sp. M4 was directly immobilized on magnetic nanoparticles (MNP) from the cell-free extract containing his-tagged AmDH through affinity attachment to give AmDH-MNPs with high yield, enzyme loading efficiency, and specific enzyme loading. AmDH-MNPs showed higher activity and productivity than the free enzyme for the asymmetric reductive amination of 4-phenyl-2-butanone 1 a and phenylacetone 1 b, producing the corresponding amines (R)-2 a,b in 99 % ee and 99 % yield, and with recycling of NADH for up to 3956 times. AmDH-MNPs were easily recycled, retaining 91 % of the original productivity in the third cycle of the reductive amination of 1 a. Coupling of immobilized AmDH and immobilized glucose dehydrogenase (GDH) for the asymmetric reductive amination of 1 a gave (R)-2 a in 99 % ee and 74 % yield, with a total turnover number (TTN) of 2940 for NADH recycling. Both immobilized enzymes showed good recyclability, retaining 81 % productivity in the third reaction cycle. The developed method with coupled immobilized AmDH and immobilized GDH for the asymmetric reductive amination of ketones is useful for the synthesis of enantiopure amines, superior to the use of coupled isolated enzymes with enhanced catalytic performance and reduced enzyme cost through catalyst recycling.
- Liu, Ji,Pang, Bryan Q. W.,Adams, Joseph P.,Snajdrova, Radka,Li, Zhi
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p. 425 - 431
(2017/02/15)
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- Method for synthesizing amphetamine drug intermediate 1-phenyl-2-aminopropane
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The invention discloses a method for synthesizing an amphetamine drug intermediate 1-phenyl-2-aminopropane. The method is as below: adding propiophenone and molybdenum chloride powder in a mixed solution of 2,5-dimethyl benzylamine and p-ethylpropiophenone, conducting heating and pressure-increased reaction, cooling, eliminating air, filtering, and conducting vacuum distillation, washing, dehydration and recrystallization to obtain 1-phenyl-2-aminopropane. Compared to the synthesis method in the background, the synthetic method greatly shortens the reaction time, and significantly increases the yield; at the same time, the invention provides a novel synthetic route, and lays a good foundation to further improve the reaction yield.
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Paragraph 0020; 0021; 0022; 0023
(2017/01/19)
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- DIRECT STEREOSPECIFIC SYNTHESIS OF UNPROTECTED AZIRIDINES FROM OLEFINS
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A method for the direct stereospecific conversion of structurally diverse mono-, di-, tri- and tetra-substituted olefins to N-H, N-alkyl, N-cycloalkyl, or N-aralkyl aziridines using a hydroxylamine amination agent with transition metal catalyst. The method is operationally simple (i.e., one-pot), scalable and fast at ambient temperature.
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- Broadening the chemical scope of laccases: Selective deprotection of N-benzyl groups
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Laccase from Trametes versicolor together with TEMPO has been found to be a very efficient system to deprotect N-benzylated primary amines, differing from previously described methods since it uses oxygen as a mild oxidant in aqueous medium. Chemoselective removal of the benzyl group was achieved with excellent yields when secondary amines and alcohol moieties were also present.
- Martínez-Montero, Lía,Díaz-Rodríguez, Alba,Gotor, Vicente,Gotor-Fernández, Vicente,Lavandera, Iván
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supporting information
p. 2794 - 2798
(2015/05/27)
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- Use of metal-accumulating plants for implementing chemical reactions
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The use of metal-accumulating plants for implementing chemical reactions.
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Page/Page column 49; 50
(2015/10/28)
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- USE OF COMPOSITIONS OBTAINED BY CALCINING PARTICULAR METAL-ACCUMULATING PLANTS FOR IMPLEMENTING CATALYTICAL REACTIONS
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The use of metal-accumulating plants for implementing chemical reactions especially catalytical reactions.
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Paragraph 0787-0793
(2016/01/25)
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- Engineering of amine dehydrogenase for asymmetric reductive amination of ketone by evolving Rhodococcus phenylalanine dehydrogenase
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Triple mutant K66Q/S149G/N262C (TM-pheDH) of Rhodococcus phenylalanine dehydrogenase (pheDH) was engineered by directed evolution as the first enzyme for the highly enantioselective reductive amination of phenylacetone 1 and 4-phenyl-2-butanone 3, giving (R)-amphetamine 2 and (R)-1-methyl-3-phenylpropylamine 4 in >98% ee, respectively. The new amine dehydrogenase TM-pheDH with special substrate specificity is a valuable addition to the amine dehydrogenase family with very limited number, for asymmetric reductive amination of ketone, an important reaction in sustainable pharmaceutical manufacturing. Molecular docking provided insight into the role of key mutations of pheDH, being useful for engineering new amine dehydrogenases with higher activity and unique substrate scope. (Chemical Equation Presented).
- Ye, Li Juan,Toh, Hui Hung,Yang, Yi,Adams, Joseph P.,Snajdrova, Radka,Li, Zhi
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p. 1119 - 1122
(2015/02/19)
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- Chiral separation of cathinone and amphetamine derivatives by HPLC/UV using sulfated β-cyclodextrin as chiral mobile phase additive
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In the last years the identification of new legal and illegal highs has become a huge challenge for the police and prosecution authorities. In an analytical context, only a few analytical methods are available to identify these new substances. Moreover, many of these recreational drugs are chiral and it is supposed that the enantiomers differ in their pharmacological potency. Since nonenantioselective synthesis is easier and cheaper, they are mainly sold as racemic mixtures. The goal of this research work was to develop an inexpensive method for the chiral separation of cathinones and amphetamines. This should help to discover if the substances are sold as racemic mixtures and give further information about their quality as well as their origin. Chiral separation of a set of 6 amphetamine and 25 cathinone derivatives, mainly purchased from various Internet shops, is presented. A LiChrospher 100 RP-18e, 250 x 4 mm, 5 μm served as the stationary phase. The chiral mobile phase consisted of methanol, water, and sulfated β-cyclodextrin. Measurements were performed under isocratic conditions in reversed phase mode using UV detection. Four model compounds of the two substance classes were used to optimize the mobile phase. Under final conditions (methanol:water 2.5:97.5 + 2% sulfated β-cyclodextrin) enantiomers of amphetamine and five derivatives were baseline separated within 23 min. In all, 17 cathinones were completely or partially chirally separated. However, as only 3 of 25 cathinones were baseline resolved, the application of this method is limited for cathinone analogs. Additionally, the results were compared with an RP-8e column. Copyright
- Taschwer, Magdalena,Seidl, Yvonne,Mohr, Stefan,Schmid, Martin G.
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p. 411 - 418
(2014/08/05)
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- Direct stereospecific synthesis of unprotected N-H and N-Me aziridines from olefins
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Despite the prevalence of the N-H aziridine motif in bioactive natural products and the clear advantages of this unprotected parent structure over N-protected derivatives as a synthetic building block, no practical methods have emerged for direct synthesis of this compound class from unfunctionalized olefins. Here, we present a mild, versatile method for the direct stereospecific conversion of structurally diverse mono-, di-, tri-, and tetrasubstituted olefins to N-H aziridines using O-(2,4-dinitrophenyl)hydroxylamine (DPH) via homogeneous rhodium catalysis with no external oxidants. This method is operationally simple (i.e., one-pot), scalable, and fast at ambient temperature, furnishing N-H aziridines in good-to-excellent yields. Likewise, N-alkyl aziridines are prepared from N-alkylated DPH derivatives. Quantum-mechanical calculations suggest a plausible Rh-nitrene pathway.
- Jat, Jawahar L.,Paudyal, Mahesh P.,Gao, Hongyin,Xu, Qing-Long,Yousufuddin, Muhammed,Devarajan, Deepa,Ess, Daniel H.,Kurti, Laszlo,Falck, John R.
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- Enantioselective hydrogenation of α,β-disubstituted nitroalkenes
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The first highly chemo- and enantioselective hydrogenation of α,β-disubstituted nitroalkenes was accomplished with rhodium/JosiPhos-J2 as a catalyst, with the yield and enantioselectivity of up to 95% and 94%, respectively. The α-chiral nitroalkanes will provide an entry to valuable chiral amphetamines which are otherwise not so easily accessed. This journal is the Partner Organisations 2014.
- Li, Shengkun,Huang, Kexuan,Zhang, Xumu
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p. 8878 - 8881
(2014/08/05)
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- Simple access to elusive α-boryl carbanions and their alkylation: An umpolung construction for organic synthesis
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The reaction of 1,1-bis(pinacolboronate) esters with alkyl halides can be effected by metal alkoxides and provides a strategy for the construction of organoboronate compounds. The reaction is found to occur by alkoxide-induced deborylation and generation of a boron-stabilized carbanion.
- Hong, Kai,Liu, Xun,Morken, James P.
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supporting information
p. 10581 - 10584
(2014/08/18)
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- Heterogeneous Ni catalyst for direct synthesis of primary amines from alcohols and ammonia
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This paper reports the synthesis of primary amines from alcohols and NH3 by an Al2O3-supported Ni nanoparticle catalyst as the first example of heterogeneous and noble-metal-free catalytic system for this reaction without additional hydrogen sources under relatively mild conditions. Various aliphatic alcohols are tolerated, and turnover numbers were higher than those of Ru-based homogeneous catalysts. The catalyst was recoverable and was reused. The effects of the Ni oxidation states and the acid-base nature of support oxides on the catalytic activity are studied. It is clarified that the surface metallic Ni sites are the catalytically active species, and the copresence of acidic and basic sites on the support surface is also indispensable for this catalytic system.
- Shimizu, Ken-Ichi,Kon, Kenichi,Onodera, Wataru,Yamazaki, Hiroshi,Kondo, Junko N.
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p. 112 - 117
(2013/03/29)
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- Investigation of one-enzyme systems in the ω-transaminase-catalyzed synthesis of chiral amines
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ω-Transaminase (TA) catalyzed asymmetric syntheses of amines were carried out in the one enzyme systems with wild-type enzymes (S)-TA from Pseudomonas aeruginosa, (S)-TA from Paracoccus denitrificans and (R)-TA from Aspergillus terreus. The scope of amine donors and aromatic carbonyl substrates was thoroughly explored. Among the range of potential amino donors, 2-propylamine, 2-butylamine and 1-phenylethylamine were found as promising candidates, which gave superior conversions in the amination reactions compared to other donors. Various prochiral aromatic ketones were accepted as substrates by the investigated enzymes. In most cases, good to excellent conversions (up to 98%) to the amine products with excellent e.e.-values (>99.9% for (S) or (R)) were obtained by the action of a single enzyme and an appropriate amino donor. (S)-TA from Paracoccus denitrificans was found to accept bulky ketones, e.g. 1-indanone, α- and β-tetralone or 2-acetonaphthone, in the asymmetric amination. In some cases the enantiomeric excesses in the amination reactions were dependent on the amino donor. More-over, the influence of the pH, temperature and cosolvents on the outcome of reactions was additionally investigated.
- Fesko, Kateryna,Steiner, Kerstin,Breinbauer, Rolf,Schwab, Helmut,Schuermann, Martin,Strohmeier, Gernot A.
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p. 103 - 110
(2013/10/22)
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- N-octanoyldimethylglycine trifluoroethyl ester, an acyl donor leading to highly enantioselective protease-catalysed kinetic resolution of amines
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The use of N-octanoyldimethylglycine trifluoroethyl ester as acyl donor in the kinetic resolution of aliphatic amines catalysed by proteases led to enantiomeric ratios >200 in most cases. The resolutions mediated by Protex 6L were shown to be much faster
- Queyroy, Severine,Vanthuyne, Nicolas,Gastaldi, Stephane,Bertrand, Michele P.,Gil, Gerard
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supporting information; experimental part
p. 1759 - 1764
(2012/08/08)
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- Enzymatic enantiomeric resolution of phenylethylamines structurally related to amphetamine
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Both enantiomers of several phenylethylamines, structurally related to amphetamine, have been prepared in good yields and excellent enantiomeric purity by enzymatic kinetic resolution using CAL-B and ethyl methoxyacetate as the acyl donor. In the case of the 4-hydroxyderivative of amphetamine (compound 4i), the S enantiomer racemized possibly in a dynamic kinetic resolution (DKR) under the enzymatic conditions used. The Royal Society of Chemistry 2011.
- Munoz, Lourdes,Rodriguez, Anna M.,Rosell, Gloria,Bosch, M. Pilar,Guerrero, Angel
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p. 8171 - 8177
(2012/01/04)
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- Chemoenzymatic dynamic kinetic resolution of primary amines catalyzed by CAL-B at 38-40°c
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The (R)-selective chemoenzymatic dynamic kinetic resolution of primary amines was performed at 38-40 °C in MTBE, in good to high yields and with high enantiomeric excesses. These reactions associating CAL-B to octanethiol as radical racemizing agent were carried out in the presence of methyl β-methoxy propanoate as acyl donor, under photochemical irradiation at 350 nm in glassware.
- Poulhes, Florent,Vanthuyne, Nicolas,Bertrand, Michele P.,Gastaldi, Stephane,Gil, Gerard
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experimental part
p. 7281 - 7286
(2011/10/10)
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- Ring opening of pymisyl-protected aziridines with organocuprates
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The pyrimidine-2-sulfonyl (pymisyl) group is introduced as a new protecting group that can be used to activate aziridines towards ring opening. It is readily introduced and removed under mild conditions. Regioselective ring opening of pymisyl-protected 2-methyl-aziridine with organocuprates gives the corresponding sulfonamides in high yields, and the pymisyl group can subsequently be removed upon treatment with a thiolate. The versatility of this new nitrogen protecting group is illustrated with a new synthesis of Selegiline, a monoamine oxidase-B inhibitor marketed for the treatment of Parkinson's disease. Easy on'easy off: The pymisyl group is introduced as a new protecting group for the activation of aziridines towards ring opening with organocuprates (see scheme). It is readily removed under very mild conditions with thiolates. The versatility of the approach is illustrated in a new synthesis of Selegiline, a drug marketed for the treatment of Parkinson's disease.
- Bornholdt, Jan,Felding, Jakob,Clausen, Rasmus P.,Kristensen, Jesper L.
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supporting information; experimental part
p. 12474 - 12480
(2010/12/25)
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- Synthesis of 2-Arylethylamines by the Curtius Rearrangement
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2-Arylethylamine derivatives were synthesized using the Curtius reaction and with three different methods of preparing the acyl azide functional group. Carbamates derived from isocyanate were convenient protecting groups for alkylation of amines. Starting from benzaldehyde, amphetamine was prepared in three steps through an oxazolidin-2-one intermediate in 62% overall yield. Copyright Taylor & Francis Group, LLC.
- Schulze, Matthias
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experimental part
p. 1461 - 1476
(2010/07/08)
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- METHOD FOR MAKING PHARMACEUTICAL COMPOUNDS
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A method of making a phenylethylamine of formula B: wherein R2, R3, R4, R5, R6, Rα, Rβ and Rn are each independently selected from hydrogen, alkyl, acyl, aryl, amido, amino acids, sugars and nucleotides. The method includes the reduction of a compound of formula A in the absence of base: wherein R2, R3, R4, R5, R6, Rα, Rβ and Rn are as defined above.
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Page/Page column 3
(2010/06/13)
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- An efficient and general synthesis of primary amines by ruthenium-catalyzed amination of secondary alcohols with ammonia
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Atom efficiency and selectivity are the key features of the first homogeneously catalyzed amination of secondary alcohols with ammonia to give the corresponding primary amines (see scheme). This novel amination method relies on the commercially available catalyst [Ru3(CO)12]/ cataCXium PCy and does not require any additional source of hydrogen.
- Imm, Sebastian,Neubert, Lorenz,Neumann, Helfried,Beller, Matthias
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supporting information; experimental part
p. 8126 - 8129
(2011/02/22)
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- Organocerium additions to proline-derived hydrazones: Synthesis of enantiomerically enriched amines
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The addition of organocerium reagents (from both organolithium and organomagnesium precursors) to chiral aldehyde hydrazones prepared from 1-aminoproline derivatives has been studied. The additions proceed in good yield and high diastereoselectivity and with good nucleophile (Me, n-Bu, i-Pr, t-Bu, Ph, etc.) and substrate scope (alkyl, alkenyl and aryl). The resulting hydrazines can be converted to amines by N-N bond cleavage through hydrogenolysis (Raney nickel) or by acylation and cleavage with Li/NH 3. The influence of the side chain on the diastereoselectivity was investigated through variation of the substituents to include more coordinating atoms (oxygen and nitrogen) as well as the removal of coordinating atoms. The SAMEMP auxiliary bearing a 2-methoxyethoxymethyl group gave the highest diastereoselectivities. Remarkably, auxiliaries bearing simple methyl and isobutyl substituents gave high selectivities as well. Hypotheses for the origin of the selectivity are presented.
- Denmark, Scott E.,Edwards, James P.,Weber, Theodor,Piotrowski, David W.
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experimental part
p. 1278 - 1302
(2010/11/02)
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- Novel carbamate cholinesterase inhibitors that release biologically active amines following enzyme inhibition
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Conjugation of the phenol derived from rivastigmine with amphetamines gave access to novel carbamate cholinesterase inhibitors. All compounds possessed increased affinity and selectivity for AChE compared to rivastigmine and were orally bioavailable. Comp
- Verheijen, Jeroen C.,Wiig, Kjesten A.,Du, Shoucheng,Connors, Stacie L.,Martin, Ashley N.,Ferreira, Jennifer P.,Slepnev, Vladimir I.,Kochendoerfer, Ulrike
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body text
p. 3243 - 3246
(2010/08/06)
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- Characterization of route specific impurities found in methamphetamine synthesized by the Leuckart and reductive amination methods
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Impurity profiling of seized methamphetamine can provide very useful information in criminal investigations and, specifically, on drug trafficking routes, sources of supply, and relationships between seizures. Particularly important is the identification of "route specific" impurities or those which indicate the synthetic method used for manufacture in illicit laboratories. Previous researchers have suggested impurities which are characteristic of the Leuckart and reductive amination (Al/Hg) methods of preparation. However, to date and importantly, these two synthetic methods have not been compared in a single study utilizing methamphetamine hydrochloride synthesized in-house and, therefore, of known synthetic origin. Using the same starting material, 1-phenyl-2-propanone (P2P), 40 batches of methamphetamine hydrochloride were synthesized by the Leuckart and reductive amination methods (20 batches per method). Both basic and acidic impurities were extracted separately and analyzed by GC/MS. From this controlled study, two route specific impurities for the Leuckart method and one route specific impurity for the reductive amination method are reported. The intra- and inter-batch variation of these route specific impurities was assessed. Also, the variation of the "target impurities" recently recommended for methamphetamine profiling is discussed in relation to their variation within and between production batches synthesized using the Leuckart and reductive amination routes.
- Kunalan, Vanitha,Daeid, Niamh Nic,Kerr, William J.,Buchanan, Hilary A. S.,McPherson, Allan R.
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experimental part
p. 7342 - 7348
(2010/04/06)
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- Synthesis and characterization of hydroxylated mesocarb metabolites for doping control
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The synthesis and method of analysis of hydroxylated mesocarb metabolites are described. Six potential hydroxylated mesocarb metabolites were prepared, characterized, and compared with the mesocarb metabolites synthesized enzymatically in vitro using human liver proteins and also compared with metabolites extracted from human urine after oral administration of mesocarb. p-Hydroxymesocarb was the most prevalent metabolite (conjugated and non-conjugated) observed. With respect to doping analysis, synthesis of p-hydroxymesocarb, the main urinary metabolite of mesocarb, and its availability as a reference material is important.
- Vahermo, Mikko,Suominen, Tina,Leinonen, Antti,Yli-Kauhaluoma, Jari
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experimental part
p. 201 - 209
(2009/05/09)
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- N-Acyl glycinates as acyl donors in serine protease-catalyzed kinetic resolution of amines. Improvement of selectivity and reaction rate
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Enzymatic kinetic resolution of aliphatic and benzylic amines leading to (S)-amides was achieved by using alkaline protease as the catalyst and N-octanoyl glycine trifluoroethyl ester as the acyl donor; enantioselectivity ranged between 4 to 244, while reaction times were dramatically shortened and ranged between 15 min to 6 h. The 2008 Royal Society of Chemistry.
- Nechab, Malek,El Blidi, Lahssen,Vanthuyne, Nicolas,Gastaldi, Stephane,Bertrand, Michele P.,Gil, Gerard
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supporting information; scheme or table
p. 3917 - 3920
(2009/06/28)
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- Instantaneous SmI2/H2O/amine mediated reduction of nitroalkanes and α,β-unsaturated nitroalkenes
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A rapid method for efficient reduction of nitroalkanes and α,β-unsaturated nitroalkenes using SmI2/H2O/amine has been developed.
- Ankner, Tobias,Hilmersson, G?ran
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p. 5707 - 5710
(2008/02/10)
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- An organo-catalytic approach to the enantioselective synthesis of (R)-selegiline
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An efficient enantioselective synthesis of (R)-selegiline has been achieved by two routes, via proline-catalyzed α-aminooxylation as well as α-amination of phenylpropanaldehyde as the key step.
- Talluri, Siva Kumar,Sudalai, Arumugam
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p. 9758 - 9763
(2008/02/12)
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- Determination of the synthetic origin of methamphetamine samples by 2H NMR spectroscopy
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Samples of methamphetamine, prepared according to the most common synthetic pathways, were submitted to natural-abundance 2H NMR spectroscopy. The deuterium content at the various sites of the molecule was found to depend on its synthetic history. The technique provides a chemical fingerprint of methamphetamine samples and can give hints to trace back the starting materials and the synthetic procedures.
- Armellin, Silvia,Brenna, Elisabetta,Frigoli, Samuele,Fronza, Giovanni,Fuganti, Claudio,Mussida, Daniele
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p. 3113 - 3117
(2008/02/09)
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