- In silico and in vitro antioxidant and anticancer activity profiles of urea and thiourea derivatives of 2,3-dihydro-1H-inden-1-amine
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Synthesis of a series of new urea and thiourea compounds have been accomplished by the reaction of 2,3-dihydro-1H-inden-1-amine with various phenyl isocyanates and isothiocyanates. These compounds were evaluated for their antioxidant activity by using 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical and nitric oxide (NO) radical scavenging assay methods including IC50 values. Some of the compounds exhibited potential activity in the two tested methods. Among the series of compounds, urea derivative linked with 4-bromo phenyl ring (4b), and thiourea derivatives bonded with phenyl ring (4e), 4-fluoro phenyl ring (4f) and 4-nitro pheyl ring (4h) were found to exhibit promising anti oxidant activity with low IC50 values. Where four of the title comounds exhibited higher bindig energies than the reference compound (Imatinib) in in silico molecular docking studies with Aromatase. All the synthesized compounds were characterized by IR, 1H, 13C NMR and mass spectral data.
- Chandrasekhar, Mandala,Rajendra, Wudayagiri,Raju, Chamarthi Naga,Seshaiah, Kalluru,Syam Prasad, Gandavaram,Umapriya, Kollu,Venkataramaiah, Chintha
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- Enantioselective synthesis of 1-aminoindene derivativesviaasymmetric Br?nsted acid catalysis
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We describe a catalytic asymmetric iminium ion cyclization reaction of simple 2-alkenylbenzaldimines using a BINOL-derived chiralN-triflyl phosphoramide. The corresponding 1-aminoindenes and tetracyclic 1-aminoindanes are formed in good yields and high enantioselectivities. Further, the chemical utility of the obtained enantiopure 1-aminoindene is demonstrated for the asymmetric synthesis of (S)-rasagiline.
- Ding, Du,Jiang, Hua-Jie,Wang, Tao,Wu, Xiang,Zhang, Ying,Zhao, Li-Ping
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supporting information
p. 9680 - 9683
(2021/09/30)
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- Engineering the large pocket of an (S)-selective transaminase for asymmetric synthesis of (S)-1-amino-1-phenylpropane
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Amine transaminases offer an environmentally benign chiral amine asymmetric synthesis route. However, their catalytic efficiency towards bulky chiral amine asymmetric synthesis is limited by the natural geometric structure of the small pocket, representing a great challenge for industrial applications. Here, we rationally engineered the large binding pocket of an (S)-selective ?-transaminase BPTA fromParaburkholderia phymatumto relieve the inherent restriction caused by the small pocket and efficiently transform the prochiral aryl alkyl ketone 1-propiophenone with a small substituent larger than the methyl group. Based on combined molecular docking and dynamic simulation analyses, we identified a non-classical substrate conformation, located in the active site with steric hindrance and undesired interactions, to be responsible for the low catalytic efficiency. By relieving the steric barrier with W82A, we improved the specific activity by 14-times compared to WT. A p-p stacking interaction was then introduced by M78F and I284F to strengthen the binding affinity with a large binding pocket to balance the undesired interactions generated by F44. T440Q further enhanced the substrate affinity by providing a more hydrophobic and flexible environment close to the active site entry. Finally, we constructed a quadruple variant M78F/W82A/I284F/T440Q to generate the most productive substrate conformation. The 1-propiophenone catalytic efficiency of the mutant was enhanced by more than 470-times in terms ofkcat/KM, and the conversion increased from 1.3 to 94.4% compared with that of WT, without any stereoselectivity loss (ee > 99.9%). Meanwhile, the obtained mutant also showed significant activity improvements towards various aryl alkyl ketones with a small substituent larger than the methyl group ranging between 104- and 230-fold, demonstrating great potential for the efficient synthesis of enantiopure aryl alkyl amines with steric hindrance in the small binding pocket.
- Liu, He,Wang, Hualei,Wei, Dongzhi,Xie, Youyu,Xu, Feng,Xu, Xiangyang,Yang, Lin
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p. 2461 - 2470
(2021/04/22)
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- Direct reductive amination of ketones with ammonium salt catalysed by Cp*Ir(iii) complexes bearing an amidato ligand
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A series of half-sandwich Ir(iii) complexes1-6bearing an amidato bidentate ligand were conveniently synthesized and applied to the catalytic Leuckart-Wallach reaction to produce racemic α-chiral primary amines. With 0.1 mol% of complex1, a broad range of ketones, including aryl ketones, dialkyl ketones, cyclic ketones, α-keto acids, α-keto esters and diketones, could be transformed to their corresponding primary amines with moderate to excellent yields (40%-95%). Asymmetric transformation was also attempted with chiral Ir complexes3-6, and 16% ee of the desired primary amine was obtained. Despite the unsatisfactory enantio-control achieved so far, the current exploration might stimulate more efforts towards the discovery of better chiral catalysts for this challenging but important transformation.
- Dai, Zengjin,Pan, Ying-Min,Wang, Shou-Guo,Yin, Qin,Zhang, Xumu
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supporting information
p. 8934 - 8939
(2021/11/04)
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- ION CHANNEL INHIBITOR COMPOUNDS FOR CANCER TREATMENT
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The present invention concerns a compound of following general formula (I): where: either R is an R1 group and R′ is an -A1-Cy1 group, or R is an -A1-Cy1 group and R′ is an R1 group, R1 particularly being H or (C1-C6)alkyl group;A1 being an —NH— radical or —NH—CH2— radical;Cy1 particularly being a phenyl group,A is a fused (hetero)aromatic ring having 5 to 7 atoms, for use for treating cancer.
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Paragraph 0261; 0262; 0263
(2021/01/25)
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- Enzymatic Primary Amination of Benzylic and Allylic C(sp3)-H Bonds
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Aliphatic primary amines are prevalent in natural products, pharmaceuticals, and functional materials. While a plethora of processes are reported for their synthesis, methods that directly install a free amine group into C(sp3)-H bonds remain unprecedented. Here, we report a set of new-to-nature enzymes that catalyze the direct primary amination of C(sp3)-H bonds with excellent chemo-, regio-, and enantioselectivity, using a readily available hydroxylamine derivative as the nitrogen source. Directed evolution of genetically encoded cytochrome P411 enzymes (P450s whose Cys axial ligand to the heme iron has been replaced with Ser) generated variants that selectively functionalize benzylic and allylic C-H bonds, affording a broad scope of enantioenriched primary amines. This biocatalytic process is efficient and selective (up to 3930 TTN and 96percent ee), and can be performed on preparative scale.
- Jia, Zhi-Jun,Gao, Shilong,Arnold, Frances H.
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supporting information
p. 10279 - 10283
(2020/07/27)
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- Kinetic Resolution of Racemic Primary Amines Using Geobacillus stearothermophilus Amine Dehydrogenase Variant
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A NADH-dependent engineered amine dehydrogenase from Geobacillus stearothermophilus (LE-AmDH-v1) was applied together with a NADH-oxidase from Streptococcus mutans (NOx) for the kinetic resolution of pharmaceutically relevant racemic α-chiral primary amines. The reaction conditions (e. g., pH, temperature, type of buffer) were optimised to yield S-configured amines with up to >99 % ee.
- Tseliou, Vasilis,Knaus, Tanja,Vilím, Jan,Masman, Marcelo F.,Mutti, Francesco G.
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p. 2184 - 2188
(2020/03/11)
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- Cerium-Catalyzed C-H Functionalizations of Alkanes Utilizing Alcohols as Hydrogen Atom Transfer Agents
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Modern photoredox catalysis has traditionally relied upon metal-to-ligand charge-transfer (MLCT) excitation of metal polypyridyl complexes for the utilization of light energy for the activation of organic substrates. Here, we demonstrate the catalytic application of ligand-to-metal charge-transfer (LMCT) excitation of cerium alkoxide complexes for the facile activation of alkanes utilizing abundant and inexpensive cerium trichloride as the catalyst. As demonstrated by cerium-catalyzed C-H amination and the alkylation of hydrocarbons, this reaction manifold has enabled the facile use of abundant alcohols as practical and selective hydrogen atom transfer (HAT) agents via the direct access of energetically challenging alkoxy radicals. Furthermore, the LMCT excitation event has been investigated through a series of spectroscopic experiments, revealing a rapid bond homolysis process and an effective production of alkoxy radicals, collectively ruling out the LMCT/homolysis event as the rate-determining step of this C-H functionalization.
- An, Qing,Chen, Yuegang,Liu, Weimin,Pan, Hui,Wang, Xin,Wang, Ziyu,Zhang, Kaining,Zuo, Zhiwei
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supporting information
p. 6216 - 6226
(2020/04/27)
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- Cobalt-Catalyzed Intermolecular Markovnikov Hydroamination of Nonactivated Olefins: N2-Selective Alkylation of Benzotriazole
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Cobalt-catalyzed Markovnikov-selective hydroamination of nonactivated olefins was developed. Hydrogen atom transfer from a catalytically generated cobalt(III)-hydride complex to the olefins proceeded regioselectively, and the nucleophilic addition of benzotriazoles occurred selectively at their N2-positions. The synthetic utility of the obtained N2-alkylated benzotriazoles as stable amine protecting groups under various reaction conditions was demonstrated, and the products were also transformed into primary amines by zinc-mediated reduction.
- Yahata, Kenzo,Kaneko, Yuki,Akai, Shuji
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p. 598 - 603
(2020/02/04)
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- Ultra-small cobalt nanoparticles from molecularly-defined Co-salen complexes for catalytic synthesis of amines
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We report the synthesis of in situ generated cobalt nanoparticles from molecularly defined complexes as efficient and selective catalysts for reductive amination reactions. In the presence of ammonia and hydrogen, cobalt-salen complexes such as cobalt(ii)-N,N′-bis(salicylidene)-1,2-phenylenediamine produce ultra-small (2-4 nm) cobalt-nanoparticles embedded in a carbon-nitrogen framework. The resulting materials constitute stable, reusable and magnetically separable catalysts, which enable the synthesis of linear and branched benzylic, heterocyclic and aliphatic primary amines from carbonyl compounds and ammonia. The isolated nanoparticles also represent excellent catalysts for the synthesis of primary, secondary as well as tertiary amines including biologically relevant N-methyl amines.
- Beller, Matthias,Chandrashekhar, Vishwas G.,Gawande, Manoj B.,Jagadeesh, Rajenahally V.,Kalevaru, Narayana V.,Kamer, Paul C. J.,Senthamarai, Thirusangumurugan,Zbo?il, Radek
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p. 2973 - 2981
(2020/03/27)
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- Method for preparing primary amine by catalyzing reductive amination of aldehyde ketone compounds
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The invention discloses a method for preparing primary amine by catalyzing reductive amination of aldehyde ketone compounds. The method comprises the following steps: 1) mixing nickel nitrate hexahydrate, citric acid and an organic solvent, carrying out heating and stirring until a colloidal material is obtained, drying the colloidal material, roasting the colloidal material in a protective atmosphere, pickling, washing and drying a roasted product, and performing a partial oxidation reaction on a dried product in an oxygen-nitrogen mixed atmosphere to obtain a catalyst for a reductive amination reaction; and 2) mixing aldehyde or ketone compounds, a methanol solution of ammonia and the reductive amination reaction catalyst, introducing hydrogen, and carrying out a reductive amination reaction. The method has the advantages of high primary amine yield, high selectivity, wide aldehyde ketone substrate range, short reaction time, mild reaction conditions, low cost, greenness, economicalperformance and the like; the used reductive amination reaction catalyst can be recycled more than 10 times, and the catalytic activity of the catalyst is not obviously changed in gram-level reactions; and the method is suitable for large-scale application.
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Paragraph 0070-0071
(2020/05/30)
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- Deconstructive Oxygenation of Unstrained Cycloalkanamines
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A deconstructive oxygenation of unstrained primary cycloalkanamines has been developed for the first time using an auto-oxidative aromatization promoted C(sp3)?C(sp3) bond cleavage strategy. This metal-free method involves the substitution reaction of cycloalkanamines with hydrazonyl chlorides and subsequent auto-oxidative annulation to in situ generate pre-aromatics, followed by N-radical-promoted ring-opening and further oxygenation by 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) and m-cholorperoxybenzoic acid (mCPBA). Consequently, a series of 1,2,4-triazole-containing acyclic carbonyl compounds were efficiently produced. This protocol features a one-pot operation, mild reaction conditions, high regioselectivity and ring-opening efficiency, broad substrate scope, and is compatible with alkaloids, osamines, and peptides, as well as steroids.
- Han, Bing,He, Yi-Heng,Pan, Jia-Hao,Wang, Yuan-Rui,Yu, Wei,Zhang, Jian-Wu
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p. 3900 - 3904
(2020/02/11)
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- Facile synthesis of controllable graphene-co-shelled reusable Ni/NiO nanoparticles and their application in the synthesis of amines under mild conditions
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The primary objective of many researchers in chemical synthesis is the development of recyclable and easily accessible catalysts. These catalysts should preferably be made from Earth-abundant metals and have the ability to be utilised in the synthesis of pharmaceutically important compounds. Amines are classified as privileged compounds, and are used extensively in the fine and bulk chemical industries, as well as in pharmaceutical and materials research. In many laboratories and in industry, transition metal catalysed reductive amination of carbonyl compounds is performed using predominantly ammonia and H2. However, these reactions usually require precious metal-based catalysts or RANEY nickel, and require harsh reaction conditions and yield low selectivity for the desired products. Herein, we describe a simple and environmentally friendly method for the preparation of thin graphene spheres that encapsulate uniform Ni/NiO nanoalloy catalysts (Ni/NiO?C) using nickel citrate as the precursor. The resulting catalysts are stable and reusable and were successfully used for the synthesis of primary, secondary, tertiary, and N-methylamines (more than 62 examples). The reaction couples easily accessible carbonyl compounds (aldehydes and ketones) with ammonia, amines, and H2 under very mild industrially viable and scalable conditions (80 °C and 1 MPa H2 pressure, 4 h), offering cost-effective access to numerous functionalized, structurally diverse linear and branched benzylic, heterocyclic, and aliphatic amines including drugs and steroid derivatives. We have also demonstrated the scale-up of the heterogeneous amination protocol to gram-scale synthesis. Furthermore, the catalyst can be immobilized on a magnetic stirring bar and be conveniently recycled up to five times without any significant loss of catalytic activity and selectivity for the product.
- Cui, Zhibing,Liu, Jianguo,Liu, Qiying,Ma, Longlong,Singh, Thishana,Wang, Chenguang,Wang, Nan,Zhu, Yuting
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supporting information
p. 7387 - 7397
(2020/11/19)
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- Chemoenzymatic Synthesis of a Chiral Ozanimod Key Intermediate Starting from Naphthalene as Cheap Petrochemical Feedstock
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Ozanimod represents a recently developed, promising active pharmaceutical ingredient (API) molecule in combating multiple sclerosis. Addressing the goal of a scalable, economically attractive, and technically feasible process for the manufacture of this drug, a novel alternative synthetic approach toward (S)-4-cyano-1-aminoindane as a chiral key intermediate for ozanimod has been developed. The total synthesis of this intermediate is based on the utilization of naphthalene as a readily accessible, economically attractive, and thus favorable petrochemical starting material. At first, naphthalene is transformed into 4-carboxy-indanone within a four-step process by means of an initial Birch reduction, followed by an isomerization of the C=C double bond, oxidative C=C cleavage, and intramolecular Friedel-Crafts acylation. The transformation of the 4-carboxy-indanone into (S)-4-cyano-1-aminoindane then represents the key step for introducing the chirality and the desired absolute S configuration. When evaluating complementary biocatalytic approaches based on the use of a lipase and transaminase, respectively, the combination of a chemical reductive amination of the 4-carboxyindanone followed by a subsequent lipase-catalyzed resolution turned out to be the most efficient route, leading to the desired key intermediate (S)-4-cyano-1-aminoindane in satisfactory yield and with excellent enantiomeric excess of 99%.
- Uthoff, Florian,L?we, Jana,Harms, Christina,Donsbach, Kai,Gr?ger, Harald
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p. 4856 - 4866
(2019/05/02)
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- Rapid and Quantitative Profiling of Substrate Specificity of ω-Transaminases for Ketones
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ω-Transaminases (ω-TAs) have gained growing attention owing to their capability for asymmetric synthesis of chiral amines from ketones. Reliable high-throughput activity assay of ω-TAs is essential in carrying out extensive substrate profiling and establishing a robust screening platform. Here we report spectrophotometric and colorimetric methods enabling rapid quantitation of ω-TA activities toward ketones in a 96-well microplate format. The assay methods employ benzylamine, a reactive amino donor for ω-TAs, as a cosubstrate and exploit aldehyde dehydrogenase (ALDH) as a reporter enzyme, leading to formation of benzaldehyde detectable by ALDH owing to concomitant NADH generation. Spectrophotometric substrate profiling of two wild-type ω-TAs of opposite stereoselectivity was carried out at 340 nm with 22 ketones, revealing subtle differences in substrate specificities that were consistent with docking simulation results obtained with cognate amines. Colorimetric readout for naked eye detection of the ω-TA activity was also demonstrated by supplementing the assay mixture with color-developing reagents whose color reaction could be quantified at 580 nm. The colorimetric assay was applied to substrate profiling of an engineered ω-TA for 24 ketones, leading to rapid identification of reactive ketones. The ALDH-based assay is expected to be promising for high-throughput screening of enzyme collections and mutant libraries to fish out the best ω-TA candidate as well as to tailor enzyme properties for efficient amination of a target ketone.
- Han, Sang-Woo,Shin, Jong-Shik
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p. 3287 - 3295
(2019/06/21)
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- Reductive amination of ketonic compounds catalyzed by Cp*Ir(III) complexes bearing a picolinamidato ligand
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Cp*Ir complexes bearing a 2-picolinamide moiety serve as effective catalysts for the direct reductive amination of ketonic compounds to give primary amines under transfer hydrogenation conditions using ammonium formate as both the nitrogen and hydrogen source. The clean and operationally simple transformation proceeds with a substrate to catalyst molar ratio (S/C) of up to 20,000 at relatively low temperature and exhibits excellent chemoselectivity toward primary amines.
- Tanaka, Kouichi,Miki, Takashi,Murata, Kunihiko,Yamaguchi, Ayumi,Kayaki, Yoshihito,Kuwata, Shigeki,Ikariya, Takao,Watanabe, Masahito
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p. 10962 - 10977
(2019/09/03)
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- METHOD FOR THE HOMOGENEOUS CATALYTIC REDUCTIVE AMINATION OF CARBONYL COMPOUNDS
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The present invention relates to a method for the reductive amination of a carbonyl compound, comprising one or more carbonyl groups amenable to reductive amination, forming the corresponding primary amine, characterized in that the reaction is carried out in the presence of a homogeneously dissolved catalyst complex K, comprising at least one metal atom from Group 8, 9 or 10 of the periodic table, bearing a bidentate phosphane ligand, a carbonyl ligand, a neutral ligand and a hydride ligand, and also an acid as co-catalyst.
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Paragraph 0212; 0219-0221
(2018/07/29)
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- Kinetic Resolution and Deracemization of Racemic Amines Using a Reductive Aminase
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The NADP(H)-dependent reductive aminase from Aspergillus oryzae (AspRedAm) was combined with an NADPH oxidase (NOX) to develop a redox system that recycles the co-factor. The AspRedAm-NOX system was applied initially for the kinetic resolution of a variety of racemic secondary and primary amines to yield S-configured amines with enantiomeric excess (ee) values up to 99 %. The addition of ammonia borane to this system enabled the efficient deracemization of racemic amines, including the pharmaceutical drug rasagiline and the natural product salsolidine, with conversions up to >98 % and >99 % ee Furthermore, by using the AspRedAm W210A variant it was possible to generate the opposite R enantiomers with efficiency comparable to, or even better than, the wildtype AspRedAm.
- Aleku, Godwin A.,Mangas-Sanchez, Juan,Citoler, Joan,France, Scott P.,Montgomery, Sarah L.,Heath, Rachel S.,Thompson, Matthew P.,Turner, Nicholas J.
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p. 515 - 519
(2018/02/15)
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- N-Alkylation of Aqueous Ammonia with Alcohols Leading to Primary Amines Catalyzed by Water-Soluble N-Heterocyclic Carbene Complexes of Iridium
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A new catalytic system for the N-monoalkylation of aqueous ammonia with a variety of alcohols was developed. Water-soluble dicationic complexes of iridium bearing N-heterocyclic carbene and diammine ligands exhibited high catalytic activity for this type of reaction on the basis of hydrogen-transfer processes without generating harmful or wasteful byproducts. Various primary amines were efficiently synthesized by using safe, inexpensive, and easily handled aqueous ammonia as a nitrogen source. For example, the reaction of 1-(4-methylphenyl)ethanol with aqueous ammonia in the presence of a water-soluble N-heterocyclic carbene complex of iridium at 150 °C for 40 h gave 1-(4-methylphenyl)ethylamine in 83 % yield.
- Fujita, Ken-Ichi,Furukawa, Shohichi,Morishima, Namino,Shimizu, Mineyuki,Yamaguchi, Ryohei
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p. 1993 - 1997
(2018/03/13)
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- Substituent effects on chiral resolutions of derivatized 1-phenylalkylamines by heptakis(2,3-di-O-methyl-6-O-tert-butyldimethylsilyl)-β-cyclodextrin GC stationary phase
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Chiral resolutions of trifluoroacetyl-derivatized 1-phenylalkylamines with different type and position of substituent were investigated by capillary gas chromatography by using heptakis(2,3-di-O-methyl-6-O-tert-butyldimethylsilyl)-β-cyclodextrin diluted in OV-1701 as a chiral stationary phase. The influence of column temperature on retention and enantioselectivity was examined. All enantiomers of meta-substituted analytes as well as fluoro-substituted analytes could be resolved. Temperature had a favorable influence on enantioselectivity for small amines with substituents at the ortho-position. The type of substituent at the stereogenic center of amines also had a crucial effect as the ethyl group led to poor enantioseparation. Among all analytes studied, trifluoroacetyl-derivatized 1-(2′-fluorophenyl)ethylamine exhibited baseline resolution with the shortest analysis time.
- Issaraseriruk, Natthapol,Sritana-anant, Yongsak,Shitangkoon, Aroonsiri
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supporting information
p. 900 - 906
(2018/05/08)
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- A stereoselective, catalytic strategy for the in-flow synthesis of advanced precursors of rasagiline and tamsulosin
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The diastereoselective, trichlorosilane-mediate reduction of imines, bearing different and removable chiral auxiliaries, in combination either with achiral bases or catalytic amounts of chiral Lewis bases, was investigated to afford immediate precursors of chiral APIs (Active Pharmaceutical Ingredients). The carbon-nitrogen double bond reduction was successfully performed in batch and in flow mode, in high yields and almost complete stereocontrol. By this metal-free approach, the formal synthesis of rasagiline and tamsulosin was successfully accomplished in micro(meso) flow reactors, under continuous flow conditions. The results of these explorative studies represent a new, important step towards the development of automated processes for the preparation of enantiopure biologically active compounds.
- Brenna, Davide,Pirola, Margherita,Raimondi, Laura,Burke, Anthony J.,Benaglia, Maurizio
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supporting information
p. 6242 - 6247
(2017/09/30)
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- Dynamic power learning split preparation (S)- 1 - amino indane
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The invention relates to a preparation method of optically pure (S)-1-aminoindane. The preparation method comprises steps as follows: 1-aminoindane is taken as a raw material, a solvent, Candida rugose lipase, an acyl donor L-(+)-O-acetyl mandelic acid and a racemization catalyst KT-02 are added to a high pressure kettle in proportion, hydrogen is introduced, all components react for a period of time, and then 1-aminoindane can be completely converted into an acetyl compound of (S)-1-aminoindane. A product is purified and subjected to acid hydrolysis and alkali free operation, (S)-1-aminoindane is obtained, and an ee value of a final product is larger than 99%. The preparation method has the characteristics that the operation is simple, the racemization catalyst is cheap and available, the raw material is completely utilized, the optical purity of the product is high and the like; the preparation method has great guidance and application value in the aspect of production and preparation of (S)-1-aminoindane.
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Paragraph 0014; 0019; 0020
(2017/07/04)
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- Simultaneous engineering of an enzyme's entrance tunnel and active site: The case of monoamine oxidase MAO-N
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A new directed evolution approach is presented to enhance the activity of an enzyme and to manipulate stereoselectivity by focusing iterative saturation mutagenesis (ISM) simultaneously on residues lining the entrance tunnel and the binding pocket. This combined mutagenesis strategy was applied successfully to the monoamine oxidase from Aspergillus Niger (MAO-N) in the reaction of sterically demanding substrates which are of interest in the synthesis of chiral pharmaceuticals based on the benzo-piperidine scaffold. Reversal of enantioselectivity of Turner-type deracemization was achieved in the synthesis of (S)-1,2,3,4-tetrahydro-1-methyl-isoquinoline, (S)-1,2,3,4-tetrahydro-1-ethylisoquinoline and (S)-1,2,3,4-tetrahydro-1-isopropylisoquinoline. Extensive molecular dynamics simulations indicate that the altered catalytic profile is due to increased hydrophobicity of the entrance tunnel acting in concert with the altered shape of the binding pocket.
- Li, Guangyue,Yao, Peiyuan,Gong, Rui,Li, Jinlong,Liu, Pi,Lonsdale, Richard,Wu, Qiaqing,Lin, Jianping,Zhu, Dunming,Reetz, Manfred T.
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p. 4093 - 4099
(2017/07/10)
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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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- Synthesis and characterization of impurities in rasagiline: A novel MAO-B inhibitor in Parkinson's disease therapy
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Rasagiline (1) is indicated as adjunctive therapy and monotherapy for treatment of Parkinson's disease approved by the FDA. During the process development of rasagiline, few processes related impurities were observed along with the final API. These impurities were identified as indanol (2), indanamine (3), allyl (4), keto (7), other isomer (6) and chloro allyl (5,5a) impurities. The present work describes the synthesis of all these impurities and characterized by 1H NMR and Mass spectral analysis.
- Maruthi Raju,Moses Babu,Venkateswara Rao
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p. 1357 - 1359
(2017/05/02)
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- A metagenomics approach for new biocatalyst discovery: Application to transaminases and the synthesis of allylic amines
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Transaminase enzymes have significant potential for the sustainable synthesis of amines using mild aqueous reaction conditions. Here a metagenomics mining strategy has been used for new transaminase enzyme discovery. Starting from oral cavity microbiome samples, DNA sequencing and bioinformatics analyses were performed. Subsequent in silico mining of a library of contiguous reads built from the sequencing data identified 11 putative Class III transaminases which were cloned and overexpressed. Several screening protocols were used and three enzymes selected of interest due to activities towards substrates covering a wide structural diversity. Transamination of functionalized cinnamaldehydes was then investigated for the production of valuable amine building blocks.
- Baud, Damien,Jeffries, Jack W. E.,Moody, Thomas S.,Ward, John M.,Hailes, Helen C.
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p. 1134 - 1143
(2017/08/14)
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- Asymmetric hydrogenation of 2,3-dihydro-1H-inden-1-one oxime and derivatives
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Asymmetric hydrogenation of 2,3-dihydro-1H-inden-1-one oxime and derivatives to produce the corresponding optically active amine has been performed in the presence of rhodium and iridium catalysts. The optimization of neutral rhodium based catalytic syste
- Maj, Anna M.,Suisse, Isabelle,Agbossou-Niedercorn, Francine
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p. 268 - 273
(2017/03/01)
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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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- PROCESS AND INTERMEDIATES FOR THE RACEMIZATION OF ENANTIOMERICALLY ENRICHED 1-AMINOINDANE
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The present invention relates to an improved process for the racemization of (S) -1-aminoindane. (S) -1-aminoindane is formed as a side product in the process of preparation (R) -1-aminoindane by enantiomeric resolution of racemic 1-aminoindane. (R) -aminoindane is a valuable intermediate in the process of preparation of rasagiline.
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Page/Page column 26
(2016/08/17)
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- (R)- SELECTIVE AMINATION
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The present invention relates to a method for the enzymatic synthesis of enantiomerically enriched (R)-amines of general formula [1][c] from the corresponding ketones of the general formula [1][a] by using novel transaminases. These novel transaminases are selected from two different groups: either from a group of some 20 proteins with sequences as specified herein, or from a group of proteins having transaminase activity and isolated from a microorganism selected from the group of organisms consisting of Rahnella aquatilis, Ochrobactrum anthropi, Ochrobactrum tritici, Sinorhizobium morelense, Curtobacterium pusiffium, Paecilomyces lilacinus, Microbacterium ginsengisoli, Microbacterium trichothecenolyticum, Pseudomonas citronellolis, Yersinia kristensenii, Achromobacter spanius, Achromobacter insolitus, Mycobacterium fortuitum, Mycobacterium frederiksbergense, Mycobacterium sacrum, Mycobacterium fluoranthenivorans, Burkhoideria sp., Burkhoideria tropica, Cosmospora episphaeria, and Fusarium oxysporum.
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Paragraph 0120; 0121; 0122
(2016/03/22)
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- Synthesis of N,O-acetals by net amide C[sbnd]N bond insertion of aldehydes into N-acyl phthalimides and N-acyl azoles
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We found that N-acyl phthalimides and several N-acylated azoles are capable of reacting with aldehydes to form O-acyl-N,O-acetals in an apparent amide C[sbnd]N bond insertion. In the context of N-acyl phthalimides, the reaction is mediated by substoichiometric amounts of sodium iodide and potassium phthalimide. DFT computations supported a proposed mechanism and provided insights into the effect of the alkali metal additive. This strategy could be used to prepare a myriad of N,O-acetals from a range of aldehydes. A one-pot procedure was also developed in which N-acyl phthalimide was generated in situ prior to forming the N,O-acetal product. The one-pot strategy was used to demonstrate that activated amides derived from imidazole, pyrazole, (benzo)triazole, and tetrazole are also amenable substrates. Collectively, these studies provide an approach to the synthesis of a variety of N,O-acetals under mild conditions from inexpensive starting materials.
- Enright, Robert N.,Grinde, Jeffrey L.,Wurtz, Lincoln I.,Paeth, Matthew S.,Wittman, Tekoa R.,Cliff, Emily R.,Sankari, Yessra T.,Henningsen, Lucas T.,Tan, Chuchen,Scanlon, Joseph D.,Willoughby, Patrick H.
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p. 6397 - 6408
(2016/09/23)
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- Direct Synthesis of Primary Amines via Ruthenium-Catalysed Amination of Ketones with Ammonia and Hydrogen
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A highly selective reductive amination of ketones to primary amines with ammonia and hydrogen using a simple ruthenium catalyst has been developed. The protocol described constitutes an efficient and direct atom-economical approach en route to α-methylbenzylamine derivatives in good to high yields. The presence of catalytic amounts of aluminum triflate turned out to be crucial for achieving high conversion towards primary amines.
- Gallardo-Donaire, Joan,Ernst, Martin,Trapp, Oliver,Schaub, Thomas
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supporting information
p. 358 - 363
(2016/04/26)
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- CATALYST COMPOUNDS
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The present invention relates to an iridium-based catalyst compound for hydrogenating reducible moieties, especially imines and iminiums, the catalyst compounds being defined by the formulas: where ring B is either itself polycyclic, or ring B together with R is polycyclic. The catalysts of the invention are particularly effective in reductive amination procedures 10 which involve the in situ generation of the imine or iminium under reductive hydrogenative conditions.
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Paragraph 0314; 0321
(2015/03/28)
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- Mechanism-Guided Engineering of ω-Transaminase to Accelerate Reductive Amination of Ketones
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Asymmetric reductive amination of ketones using ω-transaminases (ω-TAs) offers a promising alternative to the chemocatalytic synthesis of chiral amines. One fundamental challenge to the biocatalytic strategy is the very low enzyme activities for most ketones compared with native substrates (i.e., cat/KM for acetophenone). The W58L mutant afforded an efficient synthesis of enantiopure amines (i.e., >99% ee) using isopropylamine as an amino donor.
- Han, Sang-Woo,Park, Eul-Soo,Dong, Joo-Young,Shin, Jong-Shik
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p. 1732 - 1740
(2015/06/02)
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- Chiral amine synthesis using ω-transaminases: An amine donor that displaces equilibria and enables high-throughput screening
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The widespread application of ω-transaminases as biocatalysts for chiral amine synthesis has been hampered by fundamental challenges, including unfavorable equilibrium positions and product inhibition. Herein, an efficient process that allows reactions to proceed in high conversion in the absence of by-product removal using only one equivalent of a diamine donor (ortho-xylylenediamine) is reported. This operationally simple method is compatible with the most widely used (R)- and (S)-selective ω-TAs and is particularly suitable for the conversion of substrates with unfavorable equilibrium positions (e.g., 1-indanone). Significantly, spontaneous polymerization of the isoindole by-product generates colored derivatives, providing a high-throughput screening platform to identify desired ω-TA activity. ω-Transaminases (ω-TA) have been employed as biocatalysts in a simple and efficient process for the synthesis of chiral amines. A dual-function diamine donor (ortho-xylylenediamine) serves to displace challenging reaction equilibria towards product formation whilst generating intensely colored by-products, which have allowed the development of liquid-phase and colony-based assays.
- Green, Anthony P.,Turner, Nicholas J.,O'Reilly, Elaine
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supporting information
p. 10714 - 10717
(2015/05/13)
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- PROCESS FOR THE PREPARATION OF ENATIOMERICALLY PURE 1-AMINOINDAN
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The present invention relates to a process for the preparation of optically pure ( R) -1-aminoindan by a diastereomeric resolution of 1-aminoindan using N-acetyl-L-glutamic acid as a resolving agent. In another aspect, the invention relates to diastereomeric salts of (R) -1-aminoindan with N-acetyl-L-glutamic acid, and their use in the process for the preparation of rasagiline.
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- Substrate profile of an ω-transaminase from Burkholderia vietnamiensis and its potential for the production of optically pure amines and unnatural amino acids
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A new (S)-enantioselective ω-transaminase (ω-TA) gene from Burkholderia vietnamiensis G4 was functionally expressed in Escherichia coli BL21 (DE3), and the purified recombinant N-terminal His-tagged ω-TA (HBV-ω-TA) had a dimeric structure with optimum pH and temperature of 8.4 and 40 C, respectively. The enzyme showed higher activities toward aromatic amines than aliphatic amines and (S)-1-methylbenzylamine ((S)-α-MBA) was the most active amino donor. For amino acceptor, keto acids, keto esters and aldehydes were more reactive than ketones with pyruvate ethyl ester being most active. Several chiral amines and unnatural amino acids or esters were synthesized using HBV-ω-TA as the catalyst and isopropylamine or (S)-α-MBA as amino donor. Notably, HBV-ω-TA catalyzed the amino transfer to β-keto esters to give optically pure β-amino acid esters. In addition, glyoxylate was used as amino acceptor for the first time in the kinetic resolution of racemic amines and optically pure amines, such as (R)-1-methylbenzylamine, (R)-1-phenylpropylamine, (R)-2-amino-4-phenylbutane and (R)-1-aminotetraline, were obtained.
- Jiang, Jinju,Chen, Xi,Feng, Jinhui,Wu, Qiaqing,Zhu, Dunming
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- A novel synthesis of rasagiline via a chemoenzymatic dynamic kinetic resolution
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A novel synthetic route for preparing rasagiline mesylate is presented using a dynamic kinetic resolution (DKR) as the key step, catalyzed by Candida antarctica lipase B (CALB) and a Pd nanocatalyst. The chiral intermediate (R)-2,3-dihydro-1-indanamine was obtained through the DKR of the racemic aminoindan rac-1 in high yield (>90%) and excellent enantioselectivity (>99% ee). The process could be conducted on a 73 g scale at 200 g/L. Rasagiline mesylate was synthesized in 25% overall yield and excellent enantioselectivity (99.9% ee) over 7 steps.
- Ma, Guozhen,Xu, Zhongqi,Zhang, Pengfei,Liu, Jinpo,Hao, Xilin,Ouyang, Jingping,Liang, Ping,You, Song,Jia, Xian
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p. 1169 - 1174
(2014/12/10)
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- Primary amines by transfer hydrogenative reductive amination of ketones by using cyclometalated IrIII catalysts
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Cyclometalated iridium complexes are found to be versatile catalysts for the direct reductive amination (DRA) of carbonyls to give primary amines under transfer-hydrogenation conditions with ammonium formate as both the nitrogen and hydrogen source. These complexes are easy to synthesise and their ligands can be easily tuned. The activity and chemoselectivity of the catalyst towards primary amines is excellent, with a substrate to catalyst ratio (S/C) of 1000 being feasible. Both aromatic and aliphatic primary amines were obtained in high yields. Moreover, a first example of homogeneously catalysed transfer-hydrogenative DRA has been realised for β-keto ethers, leading to the corresponding β-amino ethers. In addition, non-natural α-amino acids could also be obtained in excellent yields with this method. Reduce the work! A broad range of ketones have been successfully aminated to afford primary amines under transfer-hydrogenation conditions by using ammonium formate as the amine source and 0.1 mol % of a cyclometalated IrIII catalyst (see scheme). Copyright
- Talwar, Dinesh,Salguero, Noemi Poyatos,Robertson, Craig M.,Xiao, Jianliang
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supporting information
p. 245 - 252
(2014/01/17)
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- CATALYST COMPOUNDS
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The present invention relates to an iridium-based catalyst compound for hydrogenating reducible moieties, especially imines and iminiums, the catalyst compounds being defined by the formulas: where ring B is either itself polycyclic, or ring B together with R is polycyclic. The catalysts of the invention are particularly effective in reductive amination procedures 10 which involve the in situ generation of the imine or iminium under reductive hydrogenative conditions.
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Paragraph 00163; 00170
(2013/11/05)
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- Reusable ω-transaminase sol-gel catalyst for the preparation of amine enantiomers
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Heterogeneous ω-transaminase sol-gel catalysts were prepared and characterized in terms of immobilization degree, loading capacity and catalytic behavior in the kinetic resolution of racemic 1-phenylethylamine (a model compound) with sodium pyruvate in phosphate buffer (pH 7.5). The catalyst obtained when ω-transaminase from Arthrobacter sp. was encapsulated from the aqueous solution of the enzyme, isopropyl alcohol and polyvinyl alcohol in the sol-gel matrices, consisting of the 1:5 mixture of tetramethoxysilane and methyltrialkoxysilane, proved to be optimal including the reuse and storage stabilities of the catalyst. The optimized immobilizate was shown to perform well in the kinetic resolution of four structurally different aromatic primary amines in aqueous DMSO (10, v/v-%). The enzyme preparation showed synthetic potential by enabling the catalyst reuse in five consecutive preparative scale kinetic resolutions using 100 mM 1-phenylethylamine in aqueous DMSO (10, v/v-%). It was typical to fresh catalyst preparations that the kinetic resolution tended to exceed 50% before the reaction stopped leaving the (S)-amine unreacted while thereafter in reuse the reactions stopped at 50% conversion as expectable to highly enantioselective reactions.
- P?ivi?, Mari,Kanerva, Liisa T.
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p. 1488 - 1494
(2013/09/24)
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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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- Enantioselective reduction of ketoxime ethers with borane-oxazaborolidines and synthesis of the key intermediate leading to (S)-rivastigmine
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The reduction of representative alkyl aryl (E)-ketoxime O-benzyl ethers with borane catalyzed by terpene oxazaborolidines, derived from (1R)-nopinone and (1R)-camphor, gave the corresponding amines with 82-99% ee. Oxazaborolidines derived from (1S)-2-carene and (1S)-3-carene were less selective. (S)-1-(3-Methoxyphenyl)ethanamine (94% ee) the key intermediate in the synthesis of (S)-rivastigmine, was obtained by the reduction of (E)-1-(3-methoxyphenyl) ethanone O-benzyl oxime with borane/oxazaborolidine generated from (S)-valinol.
- Pakulski, Marcin M.,Mahato, Sanjit K.,Bosiak, Mariusz J.,Krzeminski, Marek P.,Zaidlewicz, Marek
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p. 716 - 721
(2012/09/21)
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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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- Solvent-free kinetic resolution of primary amines catalyzed by Candida antarctica lipase B: Effect of immobilization and recycling stability
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Highly enantioselective (E >200) N-acylation of nine racemic primary amines with isopropyl methoxyacetate in the presence of Candida antarctica lipase B (Novozym 435) has been reported to yield the unreacted (S)-amines (ee ≥98%) and produced the (R)-amides (ee ≥95%) at 50% conversion under solvent-free conditions. One of the amines and the acyl donor have been used in an equimolar ratio at room temperature (23 °C). Under the reaction conditions, the reuse stability of Novozym 435 with 1-phenylethylamine (as a model compound) has been shown to be poor while somewhat improved stability has been observed with an in-house prepared sol-gel CAL-B catalyst.
- Paeivioe, Mari,Perkioe, Paeivi,Kanerva, Liisa T.
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experimental part
p. 230 - 236
(2012/06/15)
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- RASAGILINE AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS
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The present invention relates to Rasagiline acid addition salts having a particle size D(90) greater than 250 microns and D(50) greater than 100 microns, with the proviso that acid addition salt is not mesylate. The invention also discloses a process for the preparation of such Rasagiline acid addition salts.
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- PROCESS OF RESOLUTION OF 1-AMINOINDAN
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A process for resolution of a mixture of (R)-and (S)-enantiomers of 1-aminoindan comprising fractional crystallizing one diastereomeric acid addition salt of 1-aminoindan from a solution containing a pair of diastereomeric acid addition salts of 1-aminoindan, wherein the salt-forming acid is an optically pure chiral dicarboxylic acid selected from the group consisting of L(+)-aspartic acid, L(-)malic acid and (2R,3R)-tartaric acid, and wherein the solvent for obtaining said solution is methanol.
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Page/Page column 13
(2012/09/21)
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- 3,3′-diaryl-BINOL phosphoric acids as enantioselective extractants of benzylic primary amines
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We report that 3,3′-diaryl-BINOL phosphoric acids are effective enantioselective extractants in chiral separation methods based on reactive liquid-liquid extraction. These new extractants are capable of separating racemic benzylic primary amine substrates. The effect of the nature of the substituents at the 3,3′-positions of the host were examined as well as the structure of the substrate, together with important parameters such as the organic solvent, the pH of the aqueous phase, and the host stoichiometry. Titration of the substrate with the host was monitored by FTIR, NMR, UV-Vis, and CD spectroscopy, which provided insight into the structure of the host-guest complex involved in extraction.
- Verkuijl, Bastiaan J.V.,De Vries, Johannes G.,Feringa, Ben L.
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experimental part
p. 34 - 43
(2011/10/08)
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- Reductive amination of ketones: Novel one-step transfer hydrogenations in batch and continuous-flow mode
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Various ketones were efficiently transformed into the corresponding amines using ammonium formate in the presence of Zn dust or 10% Pd/C. The low-cost Zn dust method proved to be effective in amine formation from carbonyl groups at the benzylic side-chain position of aromatic systems, whereas 10% Pd/C was an efficient catalyst in the reductive aminations of carbonyl groups non-conjugated with any π-system. The 10% Pd/C-catalyzed reductions were performed more effectively in a continuous-flow X-Cube reactor than in the batch system.
- Falus, Péter,Boros, Zoltán,Hornyánszky, Gábor,Nagy, József,Darvas, Ferenc,ürge, László,Poppe, László
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supporting information; experimental part
p. 1310 - 1312
(2011/03/22)
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- A rapid and practical protocol for solvent-free reduction of oximes to amines with NaBH4/ZrCl4/Al2O3 system
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Solvent-free reduction of various aldoximes and ketoximes to the corresponding amines was performed easily and efficiently with NaBH4 in the presence of ZrCl4 supported on Al2O3. The reactions were carried out rapidly (within 2 min) at room temperature to afford the amines in high to excellent yields.
- Zeynizadeh, Behzad,Kouhkan, Mehri
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experimental part
p. 3448 - 3452
(2012/02/01)
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