- 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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- 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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p. 3258 - 3261
(2016/07/14)
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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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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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p. 105 - 109
(2012/06/18)
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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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- 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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- 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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- Amine preparation
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A method of making (R)-N- 1-(3-methoxyphenyl)ethyl!-3-(2-chlorobenzene)propanamine which involves reducing the appropriate amidyl or iminyl precursor with an appropriate reducing agent. The appropriate amidyl or iminyl precursor is made from a synthesis involving the use of (R)-3-methoxy-α-methylbenzylamine. A method of condensing a nitrile with a primary or secondary amine to form an imine involves the reaction of a nitrile with diisobutylaluminum hydride; and then reacting the resultant compound with a primary or secondary amine to form the imine. The process is especially useful for producing enantiomerically pure chiral imines, and, ultimately, amines. Typical such imines have the formula: STR1 wherein R, R1, R2 and R3 are independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, aryl and aralkyl.
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