22103-85-1Relevant articles and documents
Discovery of a Pyrimidinedione Derivative as a Potent and Orally Bioavailable Axl Inhibitor
Zhang, Hefeng,Peng, Xia,Dai, Yang,Shao, Jingwei,Ji, Yinchun,Sun, Yiming,Liu, Bo,Cheng, Xu,Ai, Jing,Duan, Wenhu
supporting information, p. 3956 - 3975 (2021/04/12)
The receptor tyrosine kinase Axl plays important roles in promoting cancer progression, metastasis, and drug resistance and has been identified as a promising target for anticancer therapeutics. We used molecular modeling-assisted structural optimization starting with the low micromolar potency compound 9 to discover compound 13c, a highly potent and orally bioavailable Axl inhibitor. Selectivity profiling showed that 13c could inhibit the well-known oncogenic kinase Met with equal potency to its inhibition of Axl superfamily kinases. Compound 13c significantly inhibited cellular Axl and Met signaling, suppressed Axl- and Met-driven cell proliferation, and restrained Gas6/Axl-mediated cancer cell migration or invasion. Furthermore, 13c exhibited significant antitumor efficacy in Axl-driven and Met-driven tumor xenograft models, causing tumor stasis or regression at well-tolerated doses. All these favorable data make 13c a promising therapeutic candidate for cancer treatment.
N-Ammonium Ylide Mediators for Electrochemical C-H Oxidation
Saito, Masato,Kawamata, Yu,Meanwell, Michael,Navratil, Rafael,Chiodi, Debora,Carlson, Ethan,Hu, Pengfei,Chen, Longrui,Udyavara, Sagar,Kingston, Cian,Tanwar, Mayank,Tyagi, Sameer,McKillican, Bruce P.,Gichinga, Moses G.,Schmidt, Michael A.,Eastgate, Martin D.,Lamberto, Massimiliano,He, Chi,Tang, Tianhua,Malapit, Christian A.,Sigman, Matthew S.,Minteer, Shelley D.,Neurock, Matthew,Baran, Phil S.
supporting information, p. 7859 - 7867 (2021/05/26)
The site-specific oxidation of strong C(sp3)-H bonds is of uncontested utility in organic synthesis. From simplifying access to metabolites and late-stage diversification of lead compounds to truncating retrosynthetic plans, there is a growing need for new reagents and methods for achieving such a transformation in both academic and industrial circles. One main drawback of current chemical reagents is the lack of diversity with regard to structure and reactivity that prevents a combinatorial approach for rapid screening to be employed. In that regard, directed evolution still holds the greatest promise for achieving complex C-H oxidations in a variety of complex settings. Herein we present a rationally designed platform that provides a step toward this challenge using N-ammonium ylides as electrochemically driven oxidants for site-specific, chemoselective C(sp3)-H oxidation. By taking a first-principles approach guided by computation, these new mediators were identified and rapidly expanded into a library using ubiquitous building blocks and trivial synthesis techniques. The ylide-based approach to C-H oxidation exhibits tunable selectivity that is often exclusive to this class of oxidants and can be applied to real-world problems in the agricultural and pharmaceutical sectors.
Copper-catalyzed aerobic double functionalization of benzylic C(sp3)-H bonds for the synthesis of 3-hydroxyisoindolinones
Nozawa-Kumada, Kanako,Matsuzawa, Yuta,Ono, Kanako,Shigeno, Masanori,Kondo, Yoshinori
supporting information, p. 8604 - 8607 (2021/09/02)
A copper-catalyzed aerobic 3-hydroxyisoindolinone synthesis was developed via the benzylic double C(sp3)-H functionalization of 2-alkylbenzamides. In this reaction, molecular oxygen was used as both an oxidant for C(sp3)-H functionalization and an oxygen source. Our method can be extended to diverse benzylic C(sp3)-H bonds and shows excellent functional group tolerance. This journal is
Biomimetic Asymmetric Reduction of Tetrasubstituted Olefin 2,3-Disubstituted Inden-1-ones with Chiral and Regenerable NAD(P)H Model CYNAM
Ding, Yi-Xuan,Wu, Bo,Zhou, Yong-Gui,Zhu, Zhou-Hao
supporting information, p. 7166 - 7170 (2021/09/22)
Because of the formidable development of the asymmetric reduction of tetrasubstituted olefins, an effective method is in urgent demand. Herein, through the biomimetic protocol of the coenzyme NAD(P)H, the reduction of tetrasubstituted olefin 2,3-substitut
High-purity 2 - (benzoyl) benzoyl chloride synthesis method
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Paragraph 0006; 0016; 0017, (2018/07/06)
The invention discloses a method for synthesizing 2 - (benzoyl) benzoyl chloride method, comprises the following steps: (1) under the action of a catalyst, the O benzoyl benzoic acid and thionyl chloride takes acylation reaction, the preparation of 3 - ch
The Conversion of tert-Butyl Esters to Acid Chlorides Using Thionyl Chloride
Greenberg, Jacob A.,Sammakia, Tarek
, p. 3245 - 3251 (2017/03/23)
The reaction of tert-butyl esters with SOCl2 at room temperature provides acid chlorides in unpurified yields of 89% or greater. Benzyl, methyl, ethyl, and isopropyl esters are essentially unreactive under these conditions, allowing for the selective conversion of tert-butyl esters to acid chlorides in the presence of other esters.
Synthetic method of 2-chloro-4-phenyl quinazoline
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Paragraph 0015; 0016, (2017/09/01)
The invention relates to a synthetic method of 2-chloro-4-phenyl quinazoline and belongs to the technical field of organic synthetic chemistry. The synthetic method comprises the following steps of: by taking o-benzoylbenzoic acid as a raw material, performing an acylating chlorination reaction to generate o-benzoyl benzoyl chloride; performing an amidation reaction to generate o-benzoyl benzamide; performing a Hofmann degradation reaction to generate 2-amino benzophenone; and performing an annulations reaction to generate 4-phenyl quinazoline-2(1H)-one and chlorinating the 4-phenyl quinazoline-2(1H)-one by phosphorus oxychloride to finally generate 2-chloro-4-phenyl quinazoline, wherein the total yield is 20.8%. Compared with other methods, the reagents used by the route are low in price and easily available, and the post-treatment is simple. In the reaction process, the reaction conditions and synthetic processes thereof are explored, so that a simple and feasible synthetic route is provided for synthesizing 2-chloro-4-phenyl quinazoline, thereby realizing amplified production.
Old is Gold? Nefopam Hydrochloride, a Non-opioid and Non-steroidal Analgesic Drug and Its Practical One-Pot Synthesis in a Single Solvent for Large-Scale Production
Bodireddy, Mohan Reddy,Krishnaiah, Kiran,Babu, Prashanth Kumar,Bitra, Chaithanya,Gajula, Madhusudana Rao,Kumar, Pramod
, p. 1745 - 1751 (2017/11/24)
Nefopam hydrochloride is extensively used in most of the European countries until today as an analgesic because of its non-opiate (non-narcotic) and non-steroidal action with fewer side effects compared with opioid and other analgesics, which cause more troublesome side effects. A multikilogram synthesis of nefopam hydrochloride has been achieved in one pot using a single solvent (toluene). A ≥99.9% purity of the active pharmaceutical ingredient (API) was achieved in excellent overall yield (≥79%). The one-pot, five-step synthetic process involves formation of an acid chloride (3) from benzoylbenzoic acid (2) followed by amidation (4), reduction (5), cyclization (6), and formation of the hydrochloride salt (1). The major advantages include (i) use of a single solvent, (ii) >90% conversion in each step, (iii) a cost-effective and operationally friendly process, (iv) averting the formation of genotoxic impurities, and (v) improved overall yield (≥79%) provided by the one-pot operation. For the first time, we report the characterization data of API 1, intermediates 3, 4, and 5, and also a possible impurity (5a).
Is RK-682 a promiscuous enzyme inhibitor? Synthesis and in vitro evaluation of protein tyrosine phosphatase inhibition of racemic RK-682 and analogues
Carneiro, Vania M.T.,Trivella, Daniela B.B.,Scorsato, Valéria,Beraldo, Viviane L.,Dias, Mariana P.,Sobreira, Tiago J.P.,Aparicio, Ricardo,Pilli, Ronaldo A.
, p. 42 - 54 (2015/05/13)
RK-682 (1) is a natural product known to selectively inhibit protein tyrosine phosphatases (PTPases) and is used commercially as a positive control for phosphatase inhibition in in vitro assays. Protein phosphatases are involved in several human diseases including diabetes, cancer and inflammation, and are considered important targets for pharmaceutical development. Here we report the synthesis of racemic RK-682 (rac-1) and a focused set of compounds, including racemic analogues of 1, dihydropyranones and C-acylated Meldrum's acid derivatives, the later obtained in one synthetic step from commercially available starting material. We further characterized the behavior of some representative compounds in aqueous solution and evaluated their in vitro PTPase binding and inhibition. Our data reveal that rac-1 and some derivatives are able to form large aggregates in solution, in which the aggregation capacity is dependent on the acyl side chain size. However, compound aggregation per se is not able to promote PTPase inhibition. Our data disclose a novel family of PTPase inhibitors (C-acylated Meldrum's acid derivatives) and that rac-1 and derivatives with an exposed latent negatively charged substructure (e.g.: the tetronic acid core of 1) can bind to the PTPase binding site, as well promiscuously to protein surfaces. The combined capacity of compounds to bind to proteins together with their intrinsic capacity to aggregate in solution seems essential to promote enzyme aggregation and thus, its inhibition. We also observed that divalent cations, such as magnesium frequently used in enzyme buffer solutions, can deplete the inhibitory activity of rac-1, thus influencing the enzyme inhibition experiment. Overall, these data help to characterize the mechanism of PTPase inhibition by rac-1 and derivatives, revealing that enzyme inhibition is not solely dependent on compound binding to the PTPase catalytic site as generally accepted in the literature. In addition, our results point to promiscuous mechanisms that influence significantly the in vitro evaluation of enzyme inhibition by rac-1. Therefore, we recommend caution when using natural or synthetic RK-682 (1) as an internal control for evaluating PTPase inhibition and selectivity, since many events can modulate the apparent enzyme inhibition.
Total spontaneous resolution by deracemization of isoindolinones
Yagishita, Fumitoshi,Ishikawa, Hiroki,Onuki, Tatsuo,Hachiya, Shoko,Mino, Takashi,Sakamoto, Masami
supporting information, p. 13023 - 13025 (2013/03/13)
Preferential crystallization is a powerful tool to obtain optically active materials from racemic mixtures without any chiral source, and has been utilized widely for optical resolution on large scales for example in industrial processes.[ 1] To resolve optically active materials by crystallization efficiently, dynamic preferential crystallization involving a racemization process, a so-called total spontaneous resolution, has been developed.[2] Many efforts have been invested in new variations of this method, and the racemization processes can be classified into three groups: 1) involving an intermediate enolate anion or enol at the a-position of a carbonyl group,[3] 2) involving atropisomerism of axially chiral materials,[4] and 3) involving an equilibrium reaction via an achiral intermediate.[5-7] We have now developed a new example of total spontaneous resolution of isoindolinones that involves a combination of an intramolecular equilibrium reaction via an achiral intermediate and preferential crystallization.
