- 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
-
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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- ISOINDOLINE COMPOUND, AND PREPARATION METHOD, PHARMACEUTICAL COMPOSITION, AND APPLICATION OF ISOINDOLINE COMPOUND
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The present invention relates to an isoindoline compound as represented by general formula (I) and used as a CRBN regulator, and a preparation method, a pharmaceutical composition, and an application of the isoindoline compound. Specifically, a class of polysubstituted isoindoline compound provided in the present invention, as a class of CRL4CRBN E3 ubiquitin ligase regulator having a novel structure, has good anti-tumor activity and immunoregulatory activity, and can be used for preparing drugs for treating diseases associated with a CRL4CRBN E3 ubiquitin ligase.
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-
Paragraph 0313; 0317
(2021/10/22)
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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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- A Simple Biosystem for the High-Yielding Cascade Conversion of Racemic Alcohols to Enantiopure Amines
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The amination of racemic alcohols to produce enantiopure amines is an important green chemistry reaction for pharmaceutical manufacturing, requiring simple and efficient solutions. Herein, we report the development of a cascade biotransformation to aminate racemic alcohols. This cascade utilizes an ambidextrous alcohol dehydrogenase (ADH) to oxidize a racemic alcohol, an enantioselective transaminase (TA) to convert the ketone intermediate to chiral amine, and isopropylamine to recycle PMP and NAD+ cofactors via the reversed cascade reactions. The concept was proven by using an ambidextrous CpSADH-W286A engineered from (S)-enantioselective CpSADH as the first example of evolving ambidextrous ADHs, an enantioselective BmTA, and isopropylamine. A biosystem containing isopropylamine and E. coli (CpSADH-W286A/BmTA) expressing the two enzymes was developed for the amination of racemic alcohols to produce eight useful and high-value (S)-amines in 72–99 % yield and 98–99 % ee, providing with a simple and practical solution to this type of reaction.
- Li, Zhi,Tian, Kaiyuan
-
supporting information
p. 21745 - 21751
(2020/09/21)
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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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- GZ-11608, a vesicular monoamine transporter-2 inhibitor, decreases the neurochemical and behavioral effects of methamphetamine
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Despite escalating methamphetamine use and high relapse rates, pharmacotherapeutics for methamphetamine use disorders are not available. Our iterative drug discovery program had found that R-N-(1,2-dihydroxypropyl)-2,6-cis-di-(4-methoxyphenethyl)piperidine hydrochloride (GZ-793A), a selective vesicular monoamine transporter-2 (VMAT2) inhibitor, specifically decreased methamphetamine’s behavioral effects. However, GZ-793A inhibited human-ether-a-go-go-related gene (hERG) channels, suggesting cardiotoxicity and prohibiting clinical development. The current study determined if replacement of GZ-793A’s piperidine ring with a phenylalkyl group to yield S-3-(4-methoxyphenyl)-N-(1-phenylpropan-2-yl)propan-1-amine (GZ-11608) diminished hERG interaction while retaining pharmacological efficacy. VMAT2 inhibition, target selectivity, and mechanism of GZ-11608-induced inhibition of methamphetamine-evoked vesicular dopamine release were determined. We used GZ-11608 doses that decreased methamphetamine-sensitized activity to evaluate the potential exacerbation of methamphetamine-induced dopaminergic neurotoxicity. GZ-11608-induced decreases in methamphetamine reinforcement and abuse liability were determined using self-administration, reinstatement, and substitution assays. Results show that GZ-11608 exhibited high affinity (Ki 5 25 nM) and selectivity (92–1180-fold) for VMAT2 over nicotinic receptors, dopamine transporter, and hERG, suggesting low side-effects. GZ-11608 (EC50 5 620 nM) released vesicular dopamine 25-fold less potently than it inhibited VMAT2 dopamine uptake. GZ-11608 competitively inhibited methamphetamine-evoked vesicular dopamine release (Schild regression slope 5 0.9 6 0.13). GZ-11608 decreased methamphetamine sensitization without altering striatal dopamine content or exacerbating methamphetamine-induced dopamine depletion, revealing efficacy without neurotoxicity. GZ-11608 exhibited linear pharmacokinetics and rapid brain penetration. GZ-11608 decreased methamphetamine self-administration, and this effect was not surmounted by increasing methamphetamine unit doses. GZ-11608 reduced cue- and methamphetamine-induced reinstatement, suggesting potential to prevent relapse. GZ-11608 neither served as a reinforcer nor substituted for methamphetamine, suggesting low abuse liability. Thus, GZ-11608, a potent and selective VMAT2 inhibitor, shows promise as a therapeutic for methamphetamine use disorder. SIGNIFICANCE STATEMENT GZ-11608 is a potent and selective vesicular monoamine transporter-2 inhibitor that decreases methamphetamine-induced dopamine release from isolated synaptic vesicles from brain dopaminergic neurons. Results from behavioral studies show that GZ-11608 specifically decreases methamphetamine-sensitized locomotor activity, methamphetamine self-administration, and reinstatement of methamphetamine-seeking behavior, without exhibiting abuse liability. Tolerance does not develop to the efficacy of GZ-11608 to decrease the behavioral effects of methamphetamine. In conclusion, GZ-11608 is an outstanding lead in our search for a therapeutic to treat methamphetamine use disorder.
- Lee, Na-Ra,Zheng, Guangrong,Leggas, Markos,Janganati, Venumadhav,Nickell, Justin R.,Crooks, Peter A.,Bardo, Michael T.,Dwoskin, Linda P.
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p. 526 - 543
(2019/11/19)
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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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- 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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- Identification, characterization and quantification of process-related and degradation impurities in lisdexamfetamine dimesylate: Identifiction of two new compounds
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Twelve impurities (process-related and degradation) in lisdexamfetamine dimesylate (LDX), a central nervous system (CNS) stimulant drug, were first separated and quantified by high-performance liquid chromatography (HPLC) and then identified by liquid chromatography mass spectrometry (LC-MS). The structures of the twelve impurities were further confirmed and characterized by IR, HRMS and NMR analyses. Based on the characterization data, two previously unknown impurities formed during the process development and forced degradation were proposed to be (2S)-2,6-di-(lysyl)-amino-N-[(1S)-1-methyl-2-phenyl ethyl]hexanamide (Imp-H) and (2S)-2,6-diamino-N-[(1S)-1-methyl-2-(2-hydroxyphenyl)ethyl] hexanamide (Imp-M). Furthermore, these two compounds are new. Probable mechanisms for the formation of the twelve impurities were discussed based on the synthesis route of LDX. Superior separation was achieved on a YMC-Pack ODS-AQ S5 120A silica column (250 × 4.6 mm × 5 μm) using a gradient of a mixture of acetonitrile and 0.1% aqueous methanesulfonic acid solution. The HPLC method was optimized in order to separate, selectively detect, and quantify all the impurities. The full identification and characterization of these impurities should prove useful for quality control in the manufacture of lisdexamfetamine dimesylate.
- Gao, Shenghua,Meng, Lili,Zhao, Chunjie,Zhang, Tao,Qiu, Pengcheng,Zhang, Fuli
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-
- Chiral 1,3,2-Diazaphospholenes as Catalytic Molecular Hydrides for Enantioselective Conjugate Reductions
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Secondary 1,3,2-diazaphospholenes have a polarized P?H bond and are emerging as molecular hydrides. Herein, a class of chiral, conformationally restricted methoxy-1,3,2-diazaphospholene catalysts is reported. We demonstrate their catalytic potential in asymmetric 1,4-reductions of α,β-unsaturated carbonyl derivatives, including enones, acyl pyrroles, and amides, which proceeded in enantioselectivities of up to 95.5:4.5 e.r.
- Miaskiewicz, Solène,Reed, John H.,Donets, Pavel A.,Oliveira, Caio C.,Cramer, Nicolai
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supporting information
p. 4039 - 4042
(2018/03/13)
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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
-
supporting information
p. 417 - 425
(2017/05/16)
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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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- 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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- Vesicular Monoamine Transporter-2 Ligands and Their Use in the Treatment of Psychostimulant Abuse
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The present invention relates to methods of treatment of a disease or pathology of the central nervous system, an eating disorder, or substance use disorder, drug dependence/abuse and withdrawal therefrom comprising administering at least one N-phenylalkyl amphetamine derivative and pharmaceutical compositions comprising at least one N-phenylalkyl amphetamine derivative to an individual in need thereof.
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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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- But-2-ene-1,4-diamine and But-2-ene-1,4-diol as Donors for Thermodynamically Favored Transaminase- and Alcohol Dehydrogenase-Catalyzed Processes
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Both cis- and trans-but-2-ene-1,4-diamines have been prepared and efficiently applied as sacrificial cosubstrates in enzymatic transamination reactions. The best results were obtained with the cis-diamine. The thermodynamic equilibrium of the stereoselective transamination process is shifted to the amine formation due to tautomerization of 5H-pyrrole into 1H-pyrrole, achieving high conversions (78–99%) and enantiomeric excess (up to >99%) by using a small excess of the amine donor. Furthermore, when the reaction proceeded, a strong coloration was observed due to polymerization of 1H-pyrrole. A structurally related compound, cis-but-2-ene-1,4-diol, has been utilized as cosubstrate in different alcohol dehydrogenase (ADH)-mediated bioreductions. In this case, high conversions (91–99%) were observed due to a lactonization process. Both strategies are convenient from both synthetic and atom economy points of view in the production of valuable optically active products. (Figure presented.).
- Martínez-Montero, Lía,Gotor, Vicente,Gotor-Fernández, Vicente,Lavandera, Iván
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supporting information
p. 1618 - 1624
(2016/10/13)
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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
-
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.
- -
-
Paragraph 0787-0793
(2016/01/25)
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- Synthesis of Chiral Amphetamine Derivatives by Stereospecific, Regioselective Cuprate Addition Reaction with Aziridine Phosphoramidate Compounds
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The invention includes processes for the synthesis of amphetamine, dexamphetamine, methamphetamine, derivatives of these, including their salts, and novel precursors and intermediates obtained thereby, by synthesizing aziridine phosphoramidate compounds in specified solvents at specified temperatures, and then converting to a novel aryl or aryl-alkyl phosphoramidate precursors using an organometallic compound such as a copper salt, where the novel aryl or aryl-alkyl phosphoramidate precursor is then easily converted to the target compounds using known reactions,
- -
-
Paragraph 0147; 0148
(2015/07/15)
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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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-
- 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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- 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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- 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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- 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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- The vaporization enthalpy and vapor pressure of (d)-amphetamine and of several primary amines used as standards at T /K = 298 as evaluated by correlation gas chromatography and transpiration
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The vapor pressures of several aliphatic and phenyl substituted primary amines at T/K = 298.15 are measured by transpiration studies, and their vaporization enthalpies are calculated. The results were combined with compatible literature values to evaluate both the vaporization enthalpy and vapor pressure of (d)-amphetamine by correlation gas chromatography. The results are compared to existing values either estimated or measured for racemic amphetamine. Vaporization enthalpies and vapor pressures at T/K = 298.15 of the following were measured by transpiration (kJ·mol-1, p/Pa): 1-heptanamine, (49.75 ± 0.38, 291); 1-octanamine, (55.05 ± 0.29, 108); 1-decanamine, (64.94 ± 0.32, 12); benzylamine, (54.32 ± 0.32, 88); (dl)-α-methylbenzylamine, (55.26 ± 0.33, 82); 2-phenethylamine (57.51 ± 0.35, 43). The use of several of these materials as standards resulted in a vaporization enthalpy and vapor pressure for (d)-amphetamine at T/K = 298.15 of (58.2 ± 2.7) kJ mol-1 and (38 ± 12) Pa.
- Thornton, Melissa,Chickos, James,Garist, Inna V.,Varfolomeev, Mikhail A.,Svetlov, Aleksei A.,Verevkin, Sergey P.
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p. 2018 - 2027
(2013/07/26)
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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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- BIOCATALYST FOR CATALYTIC HYDROAMINATION
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The present invention relates to a method for the enzymatic hydroamination of C—C double bonds catalyzed by enzymes structurally and/or functionally related to phenylalanine ammonia lyase (PAL) isolated from microorganisms of Petroselinum crispum, Rhodoturula glutinis and/or functional active derivatives thereof.
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Page/Page column 11
(2012/05/21)
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- ABUSE DETERRENT AND ANTI-DOSE DUMPING PHARMACEUTICAL SALTS USEFUL FOR THE TREATMENT OF ATTENTION DEFICIT/HYPERACTIVITY DISORDER
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A pharmaceutical composition comprising a drug substance consisting essentially of a pharmaceutically acceptable organic acid addition salt of an amine containing pharmaceutically active compound wherein the amine containing pharmaceutical active compound is selected from the group consisting of racemic or single isomer ritalinic acid or phenethylamine derivatives and the drug substance has a physical form selected from amorphous and polymorphic.
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Page/Page column 24-25
(2012/02/06)
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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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experimental part
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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- 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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- 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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experimental part
p. 1653 - 1658
(2011/10/13)
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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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- 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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- PROCESS FOR THE SYNTHESIS OF AMPHETAMINE DERIVATIVES
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The invention relates to a process for preparing acylated amphetamine, methamphetamine and dexamphetamine derivatives by reacting the parent amine with the to be coupled acid or a salt of the to be coupled acid which acid is protected or not protected, in the presence of an alkylphosphonic acid anhydride as coupling agent and - provided the acid (V2) was protected - the cleavage of the protecting group(s), in a one-pot reaction or in two or more separate steps.
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Page/Page column 8-10
(2010/04/28)
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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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- High specific activity (+)-amphetamine and (+)-methamphetamine
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High specific activity (+)-amphetamine and (+)-methamphetamine were prepared by reductive dechlorination of (S)-(3′,5′-dichlorophenyl)- 2-propylazide and (S)-2′6′-dichloromethamphetamine, respectively. While the latter was readily obtained by resolution o
- Lamb, Pamela B.,McElhinny, Charles J.,Sninski, Todd,Purdom, Hunter,Carroll, F. Ivy,Lewin, Anita H.
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experimental part
p. 457 - 462
(2010/07/08)
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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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