- Palladium-catalysed Cross Double Carbonylation of Amines and Alcohols: Synthesis of Oxamates
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Cross double carbonylation of amines and alcohols in the presence of PdCl2(MeCN)2/CuI catalyst under CO and O2 at room temperature gives oxamates efficiently.
- Murahashi, Shun-Ichi,Mitsue, Yo,Ike, Kazuo
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- Efficient synthesis of NK1 receptor antagonist aprepitant using a crystallization-induced diastereoselective transformation
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An efficient stereoselective synthesis of the orally active NK1 receptor antagonist Aprepitant is described. A direct condensation of N-benzyl ethanolamine with glyoxylic acid yielded a 2-hydroxy-1,4-oxazin-3-one which was activated as the corresponding trifluoroacetate. A Lewis acid mediated coupling with enantiopure (R)-1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-ol afforded a 1:1 mixture of acetal diastereomers which was converted into a single isomer via a novel crystallization-induced asymmetric transformation. The resulting 1,4-oxazin-3-one was converted via a unique and highly stereoselective one-pot process to the desired α-(fluorophenyl)morpholine derivative. Interesting and unexpected [1,2]-Wittig and [1,3]-sigmatropic rearrangements were identified during the optimization of these key steps. In the final step, a triazolinone side chain was appended to the morpholine core. The targeted clinical candidate was thus obtained in 55% overall yield over the longest linear sequence.
- Brands, Karel M. J.,Payack, Joseph F.,Rosen, Jonathan D.,Nelson, Todd D.,Candelario, Alexander,Huffman, Mark A.,Zhao, Matthew M.,Li, Jing,Craig, Bridgette,Song, Zhiguo J.,Tschaen, David M.,Hansen, Karl,Devine, Paul N.,Pye, Philip J.,Rossen, Kai,Dormer, Peter G.,Reamer, Robert A.,Welch, Christopher J.,Mathre, David J.,Tsou, Nancy N.,McNamara, James M.,Reider, Paul J.
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- PIDA/I2-Mediated α- And β-C(sp3)-H Bond Dual Functionalization of Tertiary Amines
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The α,β-C(sp3)-H bond dual functionalization of tertiary amines is still a challenging task for both organic and medicinal chemists. Herein a direct, mild, metal-free, and site-specific method mediated by PIDA/I2 was developed for α,
- Zhu, Yu,Shao, Li-Dong,Deng, Zhen-Tao,Bao, Ying,Shi, Xin,Zhao, Qin-Shi
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p. 10166 - 10174
(2018/08/01)
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- Preparation of chiral key intermediates of morpholine based neurokinin receptor antagonists by asymmetric allylic alkylation
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Abstract The preparation of optically active morpholine-2-aryl-2-allyl derivative from morpholine-2-aryl-3-ones is reported. The optically active tetrasubstituted stereocenter is introduced during a palladium promoted asymmetric allylic alkylation. The re
- Keldenich, Jér?me,Denicourt-Nowicki, Audrey,Michon, Christophe,Agbossou-Niedercorn, Francine
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p. 6424 - 6430
(2013/07/26)
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- Synthesis of a chiral key intermediate of neurokinin antagonist SSR 240600 by asymmetric allylic alkylation
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The preparation of optically active morpholine-2-aryl-2-acetaldehyde from morpholine-2-aryl-3-one is reported. The quaternary carbon is introduced during a palladium-promoted asymmetric allylic alkylation. This is a useful intermediate in the synthesis an
- Keldenich, Jér?me,Michon, Christophe,Nowicki, Audrey,Agbossou-Niedercorn, Francine
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p. 2939 - 2942
(2012/01/05)
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- Syntheses of morpholine-2,3-diones and 2-hydroxymorpholin-3-ones: Intermediates in the synthesis of aprepitant
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The preparation of morpholine-2,3-diones and 2-hydroxymorpholin-3-ones from N-substituted β-amino alcohols is reported. These were useful intermediates in the synthesis and development of aprepitant.
- Nelson, Todd D.,Rosen, Jonathan D.,Brands, Karel M.J.,Craig, Bridgette,Huffman, Mark A.,McNamara, James M.
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p. 8917 - 8920
(2007/10/03)
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- Palladium-Catalyzed Double and Single Carbonylations of β-Amino Alcohols. Selective Synthesis of Morpholine-2,3-diones and Oxazolidin-2-ones and Applications for Synthesis of α-Oxo Carboxylic Acids
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Catalytic cross double carbonylation of secondary amines and alcohols proceeds in the presence of [PdCl2(MeCN)2] and CuI under carbon monoxide (80 atm) and oxygen (5 atm). Catalytic intramolecular double carbonylation of β-amino alcohols gives morpholine-2,3-diones, which are excellent protecting compounds of amino alcohols and important precursors for biologically active nitrogen compounds. In contrast, catalytic single carbonylation of β-amino alcohols under a mixture (1 : 1) of carbon monoxide and oxygen (1.0 atm) proceeds to give oxazolidin-2-ones selectively. The reaction can be explained by assuming a mechanism which includes intramolecular nucleophilic attack of the hydroxy group of (hydroxyethyl)aminocarbonyl ligands on the CO ligand of the carbamoylpalladium(II) complexes, followed by reductive elimination to give morpholine-2,3-diones. In contrast, direct nucleophilic attack of the hydroxy group to the carbamoyl group affords oxazolidin-2-ones. As a common intermediate for the double and single carbonylations, carbamoylpalladium(II) complex has been isolated by the reaction of [PdCl2(PMe3)2] with β-amino alcohol under CO. The present double carbonylation of amino alcohols provides a novel and convenient method for synthesis of α-oxo carboxylic acids. Thus, the morpholine-2,3-diones obtained undergo reaction with Grignard reagents chemoselectively at the ester positions to give 2-substituted 2-hydroxymorpholin-3-ones, which undergo acid hydrolysis to give α-oxo carboxylic acids.
- Imada, Yasushi,Mitsue, Yo,Ike, Kazuo,Washizuka, Ken-Ichi,Murahashi, Shun-Ichi
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p. 2079 - 2090
(2007/10/03)
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