Synthesis of (<i>S</i>)-3-(<i>N</i>-Methylamino)-1-(2-thienyl)propan-1-ol:  Revisiting Eli Lilly's Resolution−Racemization−Recycle Synthesis of Duloxetine for Its Robust Processes

Fujima, Yoshito; Ikunaka, Masaya; Inoue, Toru; Matsumoto, Jun

doi:10.1021/op060118l

Cited by 51 publications

(26 citation statements)

References 12 publications

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“…2 Occasionally, the undesired isomer can be racemized so that it can be recycled. 3 However, this crystallization-based method is typically labor intensive, and suffers frequently from unreliable reproductivity. 4 Hence, new, high-yielding, low-cost chiral separation methods are a major target in current research.…”

Section: Introductionmentioning

confidence: 99%

3,3′‐diaryl‐BINOL phosphoric acids as enantioselective extractants of benzylic primary amines

2010

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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.

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Section: Introductionmentioning

confidence: 99%

3,3′‐diaryl‐BINOL phosphoric acids as enantioselective extractants of benzylic primary amines

2010

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“…(9) and (13) and that will result in non-zero enantioselectivities of forward and backward reactions. It is then interesting that some of the well-known catalysts for chiral separation, asymmetric synthesis, or even ligation (Fujima et al 2006;Sczepanski and Joyce 2014) have more stereo centers of opposite chirality in comparison to the substances on which they operate.…”

Section: Averaging Of Enantioselectivity In Catalytic Modelsmentioning

confidence: 99%

Chiral Symmetry Breaking in Peptide Systems During Formation of Life on Earth

Konstantinov

Константинова

2017

Orig Life Evol Biosph

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Chiral symmetry breaking in complex chemical systems with a large number of amino acids and a large number of similar reactions was considered. It was shown that effective averaging over similar reaction channels may result in very weak effective enantioselectivity of forward reactions, which does not allow most of the known models to result in chiral symmetry breaking during formation of life on Earth. Models with simple and catalytic synthesis of a single amino acid, formation of peptides up to length five, and sedimentation of insoluble pair of substances were considered. It was shown that depending on the model and the values of the parameters, chiral symmetry breaking may occur in up to about 10% out of all possible unique insoluble pair combinations even in the absence of any catalytic synthesis and that minimum total number of amino acids in the pair is 5. If weak enantioselective forward catalytic synthesis of amino acids is present, then the number of possible variants, in which chiral symmetry breaking may occur, increases substantially. It was shown that that the most interesting catalysts have zero or one amino acid of "incorrect" chirality. If the parameters of the model are adjusted in such a way to result in an increase of concentration of longer peptides, then catalysts with two amino acids of incorrect chirality start to appear at peptides of length five. Models of chiral symmetry breaking in the presence of epimerization were considered for peptides up to length three. It was shown that the range of parameters in which chiral symmetry breaking could occur significantly shrinks in comparison to previously considered models with peptides up to length two. An experiment of chiral symmetry breaking was proposed. The experiment consists of a three-step cycle: reversible catalytic synthesis of amino acids, reversible synthesis of peptides, and irreversible sedimentation of insoluble substances.

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“…However, catalytic systems developed by synthetic chemists only yield the product with moderate enantiomeric excesses (ee) of 80-88%, and additionally carry the risk of metal contamination [13,14,17,18]. Therefore, the predominant approach to date is via the resolution-racemization-recycle synthesis from racemic N,Ndimethyl-3-hydroxy-3-(2-thienyl)-1-propanamine (DHTP, 2b) or N-methyl-3-hydroxy-3-(2-thienyl)-1-propanamine (MHTP, 1b) to form the corresponding (S)-enantiomer, which involves multiple reaction steps and stoichiometric amount of (S)-mandelic acid as the resolution reagent [19].…”

Section: Introductionmentioning

confidence: 99%

Bioreductive production of enantiopure (S)-duloxetine intermediates catalyzed with ketoreductase ChKRED15

Ren

Liu

Pei

et al. 2015

Journal of Molecular Catalysis B: Enzymatic

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Synthesis of (S)-3-(N-Methylamino)-1-(2-thienyl)propan-1-ol: Revisiting Eli Lilly's Resolution−Racemization−Recycle Synthesis of Duloxetine for Its Robust Processes

Cited by 51 publications

References 12 publications

3,3′‐diaryl‐BINOL phosphoric acids as enantioselective extractants of benzylic primary amines

3,3′‐diaryl‐BINOL phosphoric acids as enantioselective extractants of benzylic primary amines

Chiral Symmetry Breaking in Peptide Systems During Formation of Life on Earth

Bioreductive production of enantiopure (S)-duloxetine intermediates catalyzed with ketoreductase ChKRED15

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