- De novo biosynthesis and whole-cell catalytic production of paracetamol on a gram scale in Escherichia coli
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The synthetic drug paracetamol is one of the most commonly used analgesic, antipyretic agents around the world. Global massive demand promoted its synthesis in large quantities. Chemical synthesis is the main approach for paracetamol production. However, the reaction process contributes toward environmental pollution, and the reaction conditions are harsh. Herein, we reported the construction of the paracetamol de novo biosynthetic pathway in Escherichia coli. Five enzymes from different microbial sources were heterologously expressed into E. coli to construct the APAP (1) producing strain PA1. Through protein engineering of ABH (4-aminobenzoate hydroxylase) and PANAT (arylamine N-acetyltransferase), enhancement of the host cell resistance to the substrate or final product, and utilizing synthetic protein scaffolds to optimize the metabolic flux, the engineered strain could produce 942.5 mg L-1 (6.24 mM) paracetamol in a fed-batch 5 L fermenter directly from glucose or glycerol, which circumvents the fossil fuel resource use. Moreover, we established a whole-cell cascade biocatalytic synthesis way to paracetamol and analogues. Using p-aminobenzoate as the substrate, 4.2 g L-1 (27.7 mM) paracetamol can be formed after 9 h (95% conversion rate). After metabolic engineering, enzyme molecular modification, and other optimizations, we created the biotransformation strategy to manufacture paracetamol on a gram scale. This study provides a promising green and efficient alternative to the traditional chemical manufacturing method.
- Hou, Feifei,Huang, Wei,Xian, Mo
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p. 8280 - 8289
(2021/11/01)
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- Redox-Neutral Selenium-Catalysed Isomerisation of para-Hydroxamic Acids into para-Aminophenols
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A selenium-catalysed para-hydroxylation of N-aryl-hydroxamic acids is reported. Mechanistically, the reaction comprises an N?O bond cleavage and consecutive selenium-induced [2,3]-rearrangement to deliver para-hydroxyaniline derivatives. The mechanism is studied through both 18O-crossover experiments as well as quantum chemical calculations. This redox-neutral transformation provides an unconventional synthetic approach to para-aminophenols.
- Chuang, Hsiang-Yu,Schupp, Manuel,Meyrelles, Ricardo,Maryasin, Boris,Maulide, Nuno
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p. 13778 - 13782
(2021/03/31)
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- Synthesis and pharmacological evaluation of piperidine (piperazine)-amide substituted derivatives as multi-target antipsychotics
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We report the optimisation of a series of novel amide-piperidine (piperazine) derivatives using the multiple ligand approach with dopamine and serotonin receptors. Of the derivatives, compound 11 exhibited high affinity for the D2, 5-HT1A, and 5-HT2A receptors, but low affinity for the 5-HT2C and histamine H1 receptors and human ether-a-go-go-related gene (hERG) channels. In vivo, compound 11 reduced apomorphine-induced climbing, MK-801-induced hyperactivity and DOI-induced head twitching without observable catalepsy, even at the highest dose tested. In addition, it exhibited suppression in a CAR test. Furthermore, in a novel object recognition task, it displayed procognition properties. Therefore, compound 11 is a promising candidate multi-target antipsychotic.
- Huang, Ling,Gao, Lanchang,Zhang, Xiaohua,Yin, Lei,Hu, Jintao,Song, Ting,Chen, Yin
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- A new pathway via intermediate 4-amino-3-fluorophenol for the synthesis of regorafenib
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A practical synthetic route to regorafenib, in which the target compound was obtained via a 10-step synthesis starting from 2-picolinic acid, 4-chloro-3-(trifluoromethyl)aniline, and 3-fluorophenol, is reported. Crucial to the strategy is the preparation of 4-amino-3-fluorophenol via Fries and Beckman rearrangements using an economical and practical protocol. The main advantages of the route include inexpensive starting materials and an acceptable overall yield. A scale-up experiment was carried out to provide regorafenib with 99.96% purity in 46.5% total yield.
- Du, Fangyu,Zhou, Qifan,Shi, Yajie,Yu, Miao,Sun, Wenjiao,Chen, Guoliang
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p. 576 - 586
(2019/02/01)
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- Flufenoxuron intermediate 2 - fluoro - 4 - (2 - chloro - 4 - trifluoromethyl-phenoxy) aniline synthesis method
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The invention discloses a flufenoxuron intermediate 2-fluoro-4-(2-chloro-4- trifluoromethyl phenoxyl) aniline synthesis method comprising the following steps: A) preparing 3-fluoro-4-acetyl amino phenol by acylation reaction of 3-fluoro-4-aminophenol and
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Paragraph 0023-0025
(2017/12/13)
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- COMPOUNDS FOR INHIBITING CELL PROLIFERATION IN EGFR-DRIVEN CANCERS
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The invention features compounds, pharmaceutical compositions and methods for treating patients who have an EGFR-driven cancer of Formula (I), wherein the variables are as defined herein.
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Page/Page column 58
(2013/12/03)
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- COMPOUNDS FOR INHIBITING CELL PROLIFERATION IN EGFR-DRIVEN CANCERS
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The invention features compounds, pharmaceutical compositions and methods for treating patients who have an EGFR-driven cancer of formula (I), wherein the variables are as defined herein.
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Page/Page column 56-57
(2012/11/14)
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- PROPIONAMIDE DERIVATIVES USEFUL AS ANDROGEN RECEPTOR MODULATORS
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Compounds of formula (I) wherein R1 to R4, X and A are as defined in the claims and pharmaceutically acceptable salts and esters thereof, are disclosed. The compounds of formula (I) possess utility as tissue-selective androgen receptor modulators (SARM) and are useful in hormonal therapy, e.g. in the treatment or prevention of male hypogonadism and age-related conditions such as andropause.
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- Aniline derivatives having herbicidal activity, their preparation and their use
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Compounds of formula (I): STR1 (wherein: R1 is optionally substituted alkyl, cycloalkyl, optionally substituted alkoxy, or optionally substituted alkylthio; R2 is hydrogen, optionally substituted alkyl, cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl or a group of formula --YR7 ; R3 is optionally substituted alkyl, cycloalkyl, optionally substituted alkoxy group, optionally substituted alkenyl, optionally substituted alkynyl, halogen, nitro or a group of formula --COR8, wherein R8 is hydrogen, alkyl, cycloalkyl or alkoxy; R4 and R5 are each hydrogen atom or alkyl; R6 is optionally substituted alkyl, cycloalkyl, optionally substituted alkoxy group, optionally substituted alkenyl, optionally substituted alkynyl, halogen, nitro, or a group of formula --COR8, as defined above; A, Q and X are each oxygen or sulfur; Y is a group of formula --CO--, --COO--, --CH2 O--, --CH2 S--, --CH2 CH2 O--, --CH2 CH2 S--, --CH2 CO--, --CH2 COO--, --CH(Me)COO--, --CH2 CH2 CO--, --CH2 OCO--, CH2 OCOO-- and --CH2 CH2 OCO--; R7 is optionally substituted alkyl group, cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted aralkyl, or an optionally substituted heterocycle; and m and n are each an integer from 0 to 4; and herbicidally acceptable addition salts thereof) are useful as herbicides.
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- Benzoylurea derivative and its production and use
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The present invention relates to a novel benzoylurea derivative represented by the formula; STR1 its production; and insecticides, ovicides for insects and chemosterilants for insects containing it as an active ingredient. The benzoylurea derivative is produced by reacting a benzamide compound represented by the formula, STR2 with an isocyanate compound represented by the formula, STR3
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- Benzoylurea derivative and its production and use
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The present invention relates to a novel benzoylurea derivative represented by the formula, STR1 its production and insecticides containing it as an active ingredient. The benzoylurea derivative is produced by reacting a benzamide compound represented by the formula, STR2 with an isocyanate compound represented by the formula, STR3
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