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S)-Duloxetine
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Danish Shahzad, Muhammad Faisal, Aamer Saeed
Samik Nanda et al. reported an efficient but general synthetic strategy for the enantiopure chemoenzymatic synthesis of duloxetine 2 (Schwartz et al., 2000). The chemical construction commenced with the commercially available benzaldehyde (Scheme 5.17). An asymmetric hydrocyanation reaction with Prunus armeniaca hydroxynitrile lyase (ParsHNL) and hydrogen cyanide in diisopropyl ether (DIPE) solvent furnished the respective 2-thiophene-carboxaldehyde 41 in 90% yield (ee = 97%). With the enantiopure cyanohydrins in hand, 41 is protected as its TBS (tert-butyldimethyl silyl) ether through reaction with imidazole and tert-Butyldimethylsilyl chloride at 25°C to give the protected cyanohydrin 42 in 92% yield. Compound 42 is not purified further, and so the crude mixture of 42 is subjected to DIBAL-H treatment at −78°C for 2 h, which yielded the corresponding aldehyde 43 in almost quantitative yield. The aldehyde after usual workup (no chromatographic separation is needed) is subjected to one carbon Wittig olefination with Ph3P=CH2 to afford olefin 44 in 75% yield. Compound 44 upon hydroboration with BH3. SMe2 afforded the corresponding alcohol 45 in 84% yield (no chromatographic separation is needed). Alcohol 45 is then treated with methanesulfonyl chloride (Ms-Cl) and Et3N to furnish the respective mesylate 46 in 88% yield (no chromatographic separation is needed) (Scheme 5.17). Mesylate 46 upon treatment with an aq. solution of 40% MeNH2 in refluxing THF afforded the corresponding amine 47 in 72% yield. Cleavage of silyl ether in compound 47 is accomplished by reaction with TBAF/THF to deliver aminoalcohol 12 in 90% yield (no chromatographic separation is needed). At the end, the Mitsunobu reaction of compound 12 with 1-naphthol afforded the (R)-duloxetine in 21% overall yield from 41. It is also noteworthy that out of the nine synthetic steps employed, they used chromatographic purification methods in only three steps. The synthesis is cost effective and green also, as chromatographic separation in some steps is avoided. By applying the same chemoenzymatic hydrocyanation protocol, the asymmetric fabrication of other familiar anti-depressant drugs, fluoxetine, nisoxetine, atomoxetine can be accomplished (Rej et al., 2013). Synthesis through enzyme catalyzed enantioselective hydrocyanation reaction.
Validation of Quantitative Structure-Activity Relationship (QSAR) and Quantitative Structure-Property Relationship (QSPR) approaches as alternatives to skin sensitization risk assessment
Published in Journal of Toxicology and Environmental Health, Part A, 2021
Ji Yun Kim, Kyu-Bong Kim, Byung-Mu Lee
A previous correlative study between physicochemical properties and EC3 (%) values for 212 skin sensitizers and 38 non-sensitizers was performed by Kim et al. (2019a). In addition, the physicochemical properties and EC3 (%) values of new 93 skin sensitizers and 19 non-sensitizers reported were evaluated for a total of 305 sensitizers (previous 212 + 93 additional new chemicals) and 57 non-sensitizers (previous 38 + 19 additional new chemicals)(Chemicalbook 2019; NCBI (National Center for Biotechnology Information) 2019; NIST (National Institute of Standards and Technology) 2019; USEPA (United States Environmental Protection Agency) 2019). The following new 93 skin sensitizers were selected: 4-phenylenediamine; 2,5-dichlorobenzoquinone; chlorobenzoquinone; 2,6-dichloro-1,4-benzoquinone; 2ʹ,4ʹ- dihydroxychalcone; acetic anhydride; 2-methyl-p-benzoquinone; 2,5-dimethyl-p-benzoquinone; beta-propiolactone; chloroamine T; gold chloride; 3-phenyl propenal; 2-(4-amino-2-nitro-phenylamino)-ethanol; methyl pyruvate; basil oil; clove oil; damascone; trans-beta-damascone; t-alpha damascene; 5,5-dimethyl-3-methylenedihydro-2(3 H)-furanone; glyceryl thioglycollate; lemongrass oil; maleic acid; methylanisylidene acetone; oakmoss; octinol; tetramethylthiruam disulfide; thioglycerol; trifluralin EC; palmarosa oil; phenylpropionaldehyde; spearmint oil; squalene; 2,3-dihydro-2,2,6-trimethylbenzaldehyde; 4-hexen-3-one; methanesulfonyl chloride; carbamothioic chloride, dimethyl-; phenylmethanesulfonylchloride; dinitrobenzenesulfonic acid; p-isobutyl-α-methyl hydrocinnamaldehdye; 6-methyl-3,5-heptadien-2-one; 5-amino-2-methylphenol; 4-amino-m-cresol; 2,2ʹ-[(4-amino-3-nitrophenyl)imino]diethanol; (4-ethoxyphenyl)methanol; phenethyl bromide; 5-chlorosalicylanilide; 3-cyclohexene-1-carboxylic acid; 2,6-dimethoxy-3,5-pyridinediamine HCl; ethanol dihydrochloride; 3,4-dinitrophenol; ethylene glycol monohexadecyl ether; 3-methyl-1-phenyl-5-pyrazolone; alpha-phellandrene; beta-phellandrene; tropolone; 1-octen-3-yl acetate; vanillin; isocyclogeraniol; menthadiene-7-methylformate; 2-ethylbutyraldehyde; acetylcedrene; trimethylbenzenepropanol; benzyl alcohol; cinnamyl nitrile; 4,4-dibromobenzil; butyl acrylate; methyl acrylate; acetyl isovaleryl; benzocaine; atrazine; chlorpromazine; fatty acid; glutamate; linoleic acid; streptomycin; undecylenic acid; salicylic acid; pentachlorophenol; methylhexanedione; methylhydrocinnamal; oleic acid; oxyfluorfen EC; acetyl cedrene; phenethyl isovalerate; p-chlorophenethylic alcohol; colorex 13bis; 4,4ʹ-dibromobenzil; methylbis[2-(7-oxabicyclo[4.1.0]heptan-3-yl)ethyl]phenylsilane; bisphenol A glycidyl methacrylate; 3-(3,4-methylenedioxyphenyl)-2-methylpropanal; 6-(nonanoylamino)-2-(4-sulfophenyl)hexanoate; 2,2ʹ-azobisphenol; and tridecane.