- Continuous-Flow Amide and Ester Reductions Using Neat Borane Dimethylsulfide Complex
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Reductions of amides and esters are of critical importance in synthetic chemistry, and there are numerous protocols for executing these transformations employing traditional batch conditions. Notably, strategies based on flow chemistry, especially for amide reductions, are much less explored. Herein, a simple process was developed in which neat borane dimethylsulfide complex (BH3?DMS) was used to reduce various esters and amides under continuous-flow conditions. Taking advantage of the solvent-free nature of the commercially available borane reagent, high substrate concentrations were realized, allowing outstanding productivity and a significant reduction in E-factors. In addition, with carefully optimized short residence times, the corresponding alcohols and amines were obtained in high selectivity and high yields. The synthetic utility of the inexpensive and easily implemented flow protocol was further corroborated by multigram-scale syntheses of pharmaceutically relevant products. Owing to its beneficial features, including low solvent and reducing agent consumption, high selectivity, simplicity, and inherent scalability, the present process demonstrates fewer environmental concerns than most typical batch reductions using metal hydrides as reducing agents.
- ?tv?s, Sándor B.,Kappe, C. Oliver
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p. 1800 - 1807
(2020/02/27)
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- Tackling N-Alkyl Imines with 3d Metal Catalysis: Highly Enantioselective Iron-Catalyzed Synthesis of α-Chiral Amines
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A readily activated iron alkyl precatalyst effectively catalyzes the highly enantioselective hydroboration of N-alkyl imines. Employing a chiral bis(oxazolinylmethylidene)isoindoline pincer ligand, the asymmetric reduction of various acyclic N-alkyl imines provided the corresponding α-chiral amines in excellent yields and with up to >99 % ee. The applicability of this base metal catalytic system was further demonstrated with the synthesis of the pharmaceuticals Fendiline and Tecalcet.
- Blasius, Clemens K.,Gade, Lutz H.,Heinrich, Niklas F.,Vasilenko, Vladislav
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supporting information
p. 15974 - 15977
(2020/07/04)
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- Iridium-catalyzed diastereoselective amination of alcohols with chiral: Tert-butanesulfinamide by the use of a borrowing hydrogen methodology
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An iridium-catalyzed diastereoselective amination of alcohols with chiral tert-butanesulfinamide was developed under basic conditions, affording the optically active secondary sulfinamides in high yields and diastereoselectivities. The removal of the sulfinyl group from sulfonamides allowed a facile access to a wide range of α-chiral primary amines. This synthetic strategy was further applied in the synthesis of the marketed pharmaceuticals (S)-rivastigmine and NPS R-568.
- Xi, Xiaomei,Li, Yongjie,Wang, Guannan,Xu, Guangda,Shang, Lina,Zhang, Yao,Xia, Lixin
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supporting information
p. 7651 - 7654
(2019/08/30)
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- Sulfinamide Phosphinates as Chiral Catalysts for the Enantioselective Organocatalytic Reduction of Imines
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A new type of chiral sulfinamide phosphinate catalysts with up to three stereogenic centers, readily accessible from commercially available starting materials, is reported. The naphthyl derivative SulPhos proved to be highly efficient in the organocatalyt
- Chelouan, Ahmed,Recio, Rocío,Borrego, Lorenzo G.,álvarez, Eleuterio,Khiar, Noureddine,Fernández, Inmaculada
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supporting information
p. 3258 - 3261
(2016/07/14)
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- Disulfonimide-Catalyzed Asymmetric Reduction of N-Alkyl Imines
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A chiral disulfonimide (DSI)-catalyzed asymmetric reduction of N-alkyl imines with Hantzsch esters as a hydrogen source in the presence of Boc2O has been developed. The reaction delivers Boc-protected N-alkyl amines with excellent yields and enantioselectivity. The method tolerates a large variety of alkyl amines, thus illustrating potential for a general reductive cross-coupling of ketones with diverse amines, and it was applied in the synthesis of the pharmaceuticals (S)-Rivastigmine, NPS R-568 Hydrochloride, and (R)-Fendiline. A chiral disulfonimide (DSI)-catalyzed asymmetric reduction of N-alkyl imines with Hantzsch esters as a hydrogen source in the presence of Boc2O was developed. The reaction delivers Boc-protected N-alkyl amines with excellent yields and enantioselectivity. The method was successfully applied to the synthesis of the pharmaceuticals (S)-Rivastigmine, NPS R-568 Hydrochloride, and (R)-Fendiline.
- Wakchaure, Vijay N.,Kaib, Philip S. J.,Leutzsch, Markus,List, Benjamin
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p. 11852 - 11856
(2015/10/05)
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- A two-step, one pot preparation of amines via acyl succinimides. Synthesis of the calcimimetic agents cinacalcet, NPS R-467, and NPS R-568
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Abstract A method has been developed for the preparation of amines through a process of coupling acyl succinimides derived from commercially available carboxylic acids with amines to afford the corresponding amides. These amides are then reduced in situ with either diisobutylaluminum hydride or lithium aluminum hydride. The reaction tandem of the coupling reaction followed by the reduction affords the amine in fair to good yields after purification by flash chromatography. This one-pot, two reaction tandem process has been successfully applied to the synthesis of the calcimimetic agents cinacalcet, NPS R-467, and NPS R-568.
- Gooodman, Cassie A.,Janci, Elise Marie,Onwodi, Olivia,Simpson, Chad C.,Hamaker, Christopher G.,Hitchcock, Shawn R.
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p. 4468 - 4471
(2015/06/30)
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- General strategy for large-scale synthesis of (+)-rivastigmine and (+)-NPS R-568
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An economically viable strategy for the total synthesis of (+)-rivastigmine and (+)-NPS R-568 has been reported. The strategy involves regioselective hydrogenation of diastereomerically pure bis amine to realize the desired a-methyl chiral substituted benzyl amine. The route is economical, scalable, and versatile enough to be adapted to similar classes of compounds. Taylor & Francis Group, LLC.
- Rao, Ramakrishna,Shewalkar, Mukesh Padmakar,Nandipati, Ramadevi,Yadav, Jhillu Singh,Khagga, Mukkanti,Shinde, Devanand Baburao
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experimental part
p. 589 - 598
(2011/11/29)
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- A dimethylzinc/diphenylphosphinoylimine approach to the asymmetric synthesis of the calcimimetic agent NPS R-568
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An asymmetric synthesis of the calcimimetic agent NPS R-568 using a (1R,2S)-N-benzylephedrine-promoted addition of dimethylzinc to a diphenylphosphinoylimine derived from 3-methoxybenzaldehyde is described. The enantiomeric ratio of the key amine fragment was determined to be 93:7 (86% ee), favoring the (R)-enantiomer by derivatization and chiral stationary phase HPLC analysis.
- Banerjee, Sucharita,Smith, Brad,Hitchcock, Shawn R.
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experimental part
p. 105 - 109
(2012/06/18)
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- Scope of the organocatalysed asymmetric reductive amination of ketones with trichlorosilane
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A highly active organocatalyst has been shown to affect the asymmetric reductive amination of ketones producing both aromatic and aliphatic amines. At 1 mol% catalyst loading, a series of structurally diverse chiral amines were quickly and economically prepared with good enantioselectivity and generally useful yield. The efficient synthesis of the calcimimetic (+)-NPS R-568 (67%, 89% ee) demonstrated the synthetic applicability of this methodology.
- Gautier, Franois-Moana,Jones, Simon,Li, Xianfu,Martin, Stephen J.
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p. 7860 - 7868
(2011/12/02)
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- Chemoenzymatic synthesis of the calcimimetics (+)-NPS R-568 via asymmetric reductive acylation of ketoxime intermediate
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A practical and efficient procedure for the synthesis of a potent calcimimetic (+)-NPS R-568 was developed. This procedure includes as the key step the asymmetric reductive acylation of a ketoxime intermediate catalyzed by a Pd nanocatalyst and a lipase i
- Han, Kiwon,Kim, Yunwoong,Park, Jaiwook,Kim, Mahn-Joo
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scheme or table
p. 3536 - 3537
(2010/08/07)
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- N-isopropylsulfinylimines as useful intermediates in the synthesis of chiral amines: Expeditive asymmetric synthesis of the calcimimetic (+)-NPS R-568
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(Chemical Equation Presented) An efficient and high-yielding approach for the asymmetric synthesis of calcimimetic (+)-NPS R-568 (1) has been developed. The key step of the synthesis is the highly diastereoselective addition of methyl Grignard to the (Ss
- Fernandez, Inmaculada,Valdivia, Victoria,Khiar, Noureddine
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p. 745 - 748
(2008/09/18)
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- Synthesis and biological activity of allosteric modulators of GABA B receptors, Part 1. N-(Phenylpropyl)-1-arylethylamines
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A series of 15 analogues of fendiline, and 34 derivatives of N-(3-phenylpropyl)-1-arylethylamine have been prepared for evaluation as positive allosteric modulators of GABAB receptors. The most active (EC50, 10 nM) was N-(3,3-diphenylpropyl)-1-(3-chloro-4-methoxyphenyl) ethylamine 6g. CSIRO 2006.
- Kerr, David I. B.,Ong, Jennifer,Perkins, Michael V.,Prager, Rolf H.,Puspawati, Ni Made
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p. 445 - 456
(2007/10/03)
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- Enantioselective synthesis of primary 1-(aryl)alkylamines by nucleophilic 1,2-addition of organolithium reagents to hydroxyoxime ethers and application to asymmetric synthesis of G-protein-coupled receptor ligands
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(E)-Arylaldehyde oxime ethers bearing a (1S)-2-hydroxy-1-phenylethyl or (2R)-1-hydroxy-2-phenylethyl group as a chiral auxiliary, both derived from a single precursor, methyl (R)-mandelate, underwent nucleophilic addition with organolithium reagents via six-membered chelates to give the diastereomerically enriched (R)- and (S)-adducts, respectively, which, after chiral auxiliary removal by reductive N-O bond cleavage, led to the corresponding (R)- and (S)-1-(aryl)ethylamines. This organolithium addition protocol using methyllithium was applied in an enantiodivergent fashion to the preparation of both enantiomers of 1-(2-hydroxyphenyl)ethylamine, which has been previously used as an efficient chiral auxiliary for the synthesis of natural products in this laboratory. The synthetic utility of this methodology involving diastereoselective methyl addition was demonstrated by further application to the asymmetric synthesis of a new type of calcium receptor agonist (calcimimetics), (R)-(+)-NPS R-568 and its thio analogue. Furthermore, diastereoselective vinylation was accomplished by application of the hydroxy oxime ether-based protocol using vinyllithium, which allowed the development of the enantioselective synthesis of the NK-1 receptor antagonists, (+)-CP-99,994 and (+)-CP-122,721.
- Atobe, Masakazu,Yamazaki, Naoki,Kibayashi, Chihiro
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p. 5595 - 5607
(2007/10/03)
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- Method of screening for calcium receptor-active molecules
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Method and composition useful for treating a patient having a disease characterized by an abnormal level of one or more components, the activity of which is regulated or affected by activity of one or more inorganic-ion receptor. Novel compounds useful in
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Page column 49
(2008/06/13)
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- Nucleophilic addition of methyllithium to chiral oxime ethers: Asymmetric preparation of 1-(aryl)ethylamines and application to a synthesis of calcimimetics (+)-NPS R-568 and its thio analogue
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Chiral (E)-arylaldehyde oxime ethers, prepared using (R)-1-phenyl-1,2-ethanediol as a chiral auxiliary, undergo nucleophilic addition with methyllithium to give diastereomerically enriched O-alkyl hydroxylamines which, after reductive N-O bond cleavage, lead to the corresponding (R)-1-(aryl)ethylamines. This methodology has been applied to the enantioselective synthesis of a new type of arylalkylamine calcimimetics (R)-(+)-NPS R-568 and its thio analogue.
- Yamazaki, Naoki,Atobe, Masakazu,Kibayashi, Chihiro
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p. 5029 - 5032
(2007/10/03)
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- Calcium receptor-active molecules
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The present invention relates to the different roles inorganic ion receptors have in cellular and body processes. The present invention features: (1) molecules which can modulate one or more inorganic ion receptor activities, preferably the molecule can mimic or block an effect of an extracellular ion on a cell having an inorganic ion receptor, more preferably the extracellular ion is Ca2+and the effect is on a cell having a calcium receptor; (2) inorganic ion receptor proteins and fragments thereof, preferably calcium receptor proteins and fragments thereof; (3) nucleic acids encoding inorganic ion receptor proteins and fragments thereof, preferably calcium receptor proteins and fragments thereof; (4) antibodies and fragments thereof, targeted to inorganic ion receptor proteins, preferably calcium receptor protein; and (5) uses of such molecules, proteins, nucleic acids and antibodies.
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- Calcium receptor-active molecules
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The present invention relates to the different roles inorganic ion receptors have in cellular and body processes. The present invention features: (1) molecules which can modulate one or more inorganic ion receptor activities, preferably the molecule can mimic or block an effect of an extracellular ion on a cell having an inorganic ion receptor, more preferably the extracellular ion is Ca2+ and the effect is on a cell having a calcium receptor; (2) inorganic ion receptor proteins and fragments thereof, preferably calcium receptor proteins and fragments thereof; (3) nucleic acids encoding inorganic ion receptor proteins and fragments thereof, preferably calcium receptor proteins and fragments thereof; (4) antibodies and fragments thereof, targeted to inorganic ion receptor proteins, preferably calcium receptor protein; and (5) uses of such molecules, proteins, nucleic acids and antibodies.
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- Calcium receptor-active molecules
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The present invention relates to the different roles inorganic ion receptors have in cellular and body processes. The present invention features: (1) molecules which can modulate one or more inorganic ion receptor activities, preferably the molecule can m
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- Synthesis of NPS R-568 utilizing titanium-catalyzed asymmetric hydrosilylation
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The enantioselective hydrosilylation of imines catalyzed by an (EBTHI) Ti (EBTHI=ethylene-bis(η5-tetrahydroindenyl) species was applied to the synthesis of NPS R-568, an active compound for the treatment of hyperparathyroidism.
- Hansen, Marcus C.,Buchwald, Stephen L.
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p. 2033 - 2034
(2007/10/03)
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- The addition of amines to diisobutylaluminum-imine complexes. Preparation of NPS R-568 hydrochloride
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A facile procedure for the preparation of secondary and tertiary amines from nitriles has been developed. The addition of amines to diisobutylaluminum-imine complexes derived by treating nitriles with DIBAL-H was found to proceed in moderate to good yield
- Barmore, Robert M.,Logan, Sarah R.,Van Wagenen, Bradford C.
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p. 3451 - 3454
(2007/10/03)
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- Calcium receptor-active molecules
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The present invention relates to the different roles inorganic ion receptors have in cellular and body processes. The present invention features: (1) molecules which can modulate one or more inorganic ion receptor activities, preferably the molecule can mimic or block an effect of an extracellular ion on a cell having an inorganic ion receptor, more preferably the extracellular ion is Ca2+ and the effect is on a cell having a calcium receptor; (2) inorganic ion receptor proteins and fragments thereof, preferably calcium receptor proteins and fragments thereof; (3) nucleic acids encoding inorganic ion receptor proteins and fragments thereof, preferably calcium receptor proteins and fragments thereof; (4) antibodies and fragments thereof, targeted to inorganic ion receptor proteins, preferably calcium receptor protein; and (5) uses of such molecules, proteins, nucleic acids and antibodies.
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