cas 879088-41-2, 4-chloro-3-(pyridin-2-yl)aniline

Articles about 879088-41-2Total 26 be found

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Elucidation of Distinct Modular Assemblies of Smoothened Receptor by Bitopic Ligand Measurement
Class F G protein-coupled receptors are characterized by a large extracellular domain (ECD) in addition to the common transmembrane domain (TMD) with seven α-helixes. For smoothened receptor (SMO), structural studies revealed dissected ECD and TMD, and th
Zhao, Fei,Wu, Yiran,Zhou, Fang,Xue, Dongxiang,Zhao, Simeng,Lu, Wanglong,Liu, Xiaoyan,Hu, Tao,Qiu, Yanli,Li, Rongyan,Gu, Tangjie,Xu, Yueming,Xu, Fei,Zhong, Guisheng,Jiang, Zhongxing,Zhao, Suwen,Tao, Houchao
supporting information
p. 13830 - 13840
(2021/09/28)

Preparation method of vimodegil
The invention provides a preparation method of vimodegil. 2-chloro-5-nitroacetophenone is used as a raw material; 5-oxo-5-(2-chloro-5-nitrophenyl) n-valeraldehyde is prepared through an addition reaction between 2-chloro-5-nitroacetophenone and acrolein,
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Paragraph 0077-0082; 0090-0091

(2020/05/05)

Smooth receptor ligand
The invention relates to the technical field of biology, particularly to a smooth receptor ligand, and provides a smooth receptor ligand or an isomer prodrug, a solvate and a pharmaceutically acceptable salt thereof, wherein the structural formula of the smooth receptor ligand is A-linker-B, A is an extracellular domain ligand structure, B is a transmembrane domain ligand structure, and Linker isa linear subunit inactive to the smooth receptor. According to the novel double-end small molecule ligand for the smooth receptor, by combining the crystal structure data of the smooth receptor, a linker is introduced into the proper sites of an extracellular domain ligand and a transmembrane domain ligand to obtain brand-new double-end ligand small molecules, so that the interaction between the ligand and the receptor and the biological activity of the ligand are enhanced.
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Paragraph 0085; 0252; 0260; 0281

(2020/04/01)

Divergent Late-Stage (Hetero)aryl C?H Amination by the Pyridinium Radical Cation
(Hetero)arylamines constitute some of the most prevalent functional molecules, especially as pharmaceuticals. However, structurally complex aromatics currently cannot be converted into arylamines, so instead, each product isomer must be assembled through a multistep synthesis from simpler building blocks. Herein, we describe a late-stage aryl C?H amination reaction for the synthesis of complex primary arylamines that other reactions cannot access directly. We show and rationalize through a mechanistic analysis the reasons for the wide substrate scope and the constitutional diversity of the reaction, which gives access to molecules that would not have been readily available otherwise.
Ham, Won Seok,Hillenbrand, Julius,Jacq, Jér?me,Genicot, Christophe,Ritter, Tobias
supporting information
p. 532 - 536
(2019/01/04)

A [...] synthesis of intermediates method and application
The invention relates to a method for synthesizing intermediate [...] and application, which belongs to the field of organic synthesis, in particular to intermediate 2 - (2 - chloro - 5 - nitrophenyl) pyridine (i.e. compound A) preparation process, compri
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Paragraph 0033; 0034; 0035; 0036

(2019/03/28)

Selective Late-Stage Oxygenation of Sulfides with Ground-State Oxygen by Uranyl Photocatalysis
Oxygenation is a fundamental transformation in synthesis. Herein, we describe the selective late-stage oxygenation of sulfur-containing complex molecules with ground-state oxygen under ambient conditions. The high oxidation potential of the active uranyl cation (UO22+) enabled the efficient synthesis of sulfones. The ligand-to-metal charge transfer process (LMCT) from O 2p to U 5f within the O=U=O group, which generates a UV center and an oxygen radical, is assumed to be affected by the solvent and additives, and can be tuned to promote selective sulfoxidation. This tunable strategy enabled the batch synthesis of 32 pharmaceuticals and analogues by late-stage oxygenation in an atom- and step-efficient manner.
Li, Yiming,Rizvi, S. Aal-e-Ali,Hu, Deqing,Sun, Danwen,Gao, Anhui,Zhou, Yubo,Li, Jia,Jiang, Xuefeng
supporting information
p. 13499 - 13506
(2019/08/21)

Synthetic Path To Pharmaceutically Acceptable Vismodegib
The present invention relates to a new route of synthesis to obtain pharmaceutically acceptable Vismodegib. In addition, besides the synthesis also suitable pharmaceutical compositions and the use of the compound for the treatment of basal-cell carcinomas
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Paragraph 0031; 0044; 0047; 0051

(2018/10/19)

Method for preparing erivedge by adopting microchannel reaction device
The invention discloses a method for preparing erivedge by adopting a microchannel reaction device. The method comprises the following steps: by using 2-phenylpyridine as a starting material, preparing an important intermediate 4-chloro-3-(pyridine-2-yl) aniline by metal catalysis amination, oxidation and reduction reaction in sequence, finally carrying out oxidation and amidation reaction with 2-chloro-1-methyl-4-(methylsulfonyl)benzene by two-step continuous flow in the novel microchannel reaction device, and preparing the erivedge. The microchannel reaction device has the characteristics ofcheap price, convenience in transportation and cleaning, higher heat and mass transfer efficiency and easier industrial amplification and the like. Compared with the prior art, the synthesis method has the advantages that the starting material is simple and cheap and is easy to obtain, the process is concise, the production cost can be effectively reduced, and the adaptability to industrial production is achieved.
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Paragraph 0039; 0040; 0041; 0047; 0052

(2018/06/21)

Preparation method of vismodegib
The invention relates to a preparation method of vismodegib. The preparation method of the vismodegib comprises the following steps: taking 2-chlorine-5-nitroacetophenone as a starting material, performing 1,4-addition reaction on the 2-chlorine-5-nitroac
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Paragraph 0078-0088

(2017/10/07)

Palladium-Catalyzed ortho-Selective C-H Chlorination of Benzamide Derivatives under Anodic Oxidation Conditions
The palladium-catalyzed ortho-selective chlorination of N-quinolinylbenzamide derivatives with hydrochloric acid was achieved under anodic oxidation conditions. The use of 5,7-dichloro-8-quinolinyl group as directing group was effective for the selective
Konishi, Miki,Tsuchida, Kazuya,Sano, Katsuya,Kochi, Takuya,Kakiuchi, Fumitoshi
p. 8716 - 8724
(2017/08/23)

Synthesis method of vismodegib
The invention discloses a synthesis method of vismodegib. The method comprises the following reactions: firstly, enabling 2-chloro-5-nitrophenyl boronic acid and 2-bromopyridine to make a coupled reaction to generate an intermediate 2-(2-chloro-5-nitro) phenylpyridine; reducing nitro in the 2-(2-chloro-5-nitro) phenylpyridine to amino so as to obtain 2-(2-chloro-5-amino) phenylpyridine; finally, enabling the 2-(2-chloro-5-amino) phenylpyridine and 2-chloro-4-methyl sulfuryl benzaldehyde to make a catalytic reaction to generate the vismodegib. The synthesis method is low in price of raw materials, easy in raw material obtaining, simple and convenient to operate and less in consumption of a catalyst; the reaction product is high in yield, reaction conditions are mild, and aftertreatment is simple in technology and mainly adopts column separation, so that industrial mass production can be realized.
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Paragraph 0032; 0033; 0034

(2017/07/19)

Discovery of 1-(3-aryl-4-chlorophenyl)-3-(p-aryl)urea derivatives against breast cancer by inhibiting PI3K/Akt/mTOR and Hedgehog signalings
PI3K/Akt/mTOR and hedgehog (Hh) signalings are two important pathways in breast cancer, which are usually connected with the drug resistance and cancer migration. Many studies indicated that PI3K/Akt/mTOR inhibitors and Hh inhibitors displayed synergistic effects, and the combination of the two signaling drugs could delay drug resistance and inhibit cancer migration in breast cancer. Therefore, the development of molecules simultaneously inhibiting these two pathways is urgent needed. Based on the structures of PI3K inhibitor buparlisib and Hh inhibitor vismodegib, a series of hybrid structures were designed and synthesized utilizing rational drug design and computer-based drug design. Several compounds displayed excellent antiproliferative activities against several breast cancer cell lines, including triple-negative breast cancer (TNBC) MDA-MB-231 cell. Further mechanistic studies demonstrated that the representative compound 9i could inhibit both PI3K/Akt/mTOR and hedgehog (Hh) signalings by inhibiting the phosphorylation of S6K and Akt as well as decreasing the SAG elevated expression of Gli1. Compound 9i could also induce apoptosis remarkably in T47D and MDA-MB-231 cells. In the transwell assay, 9i showed significant inhibition on the migration of MDA-MB-231.
Li, Wenlu,Sun, Qinsheng,Song, Lu,Gao, Chunmei,Liu, Feng,Chen, Yuzong,Jiang, Yuyang
p. 721 - 733
(2017/11/01)

Design, Synthesis, and Structure-Activity Relationship of Tetrahydropyrido[4,3-d]pyrimidine Derivatives as Potent Smoothened Antagonists with in Vivo Activity
Medulloblastoma is one of the most prevalent brain tumors in children. Aberrant hedgehog (Hh) pathway signaling is thought to be involved in the initiation and development of medulloblastoma. Vismodegib, the first FDA-approved cancer therapy based on inhibition of aberrant hedgehog signaling, targets smoothened (Smo), a G-protein coupled receptor (GPCR) central to the Hh pathway. Although vismodegib exhibits promising therapeutic efficacy in tumor treatment, concerns have been raised from its nonlinear pharmacokinetic (PK) profiles at high doses partly due to low aqueous solubility. Many patients experience adverse events such as muscle spasms and weight loss. In addition, drug resistance often arises among tumor cells during treatment with vismodegib. There is clearly an urgent need to explore novel Smo antagonists with improved potency and efficacy. Through a scaffold hopping strategy, we have identified a series of novel tetrahydropyrido[4,3-d]pyrimidine derivatives, which exhibited effective inhibition of Hh signaling. Among them, compound 24 is three times more potent than vismodegib in the NIH3T3-GRE-Luc reporter gene assay. Compound 24 has a lower melting point and much greater solubility compared with vismodegib, resulting in linear PK profiles when dosed orally at 10, 30, and 100 mg/kg in rats. Furthermore, compound 24 showed excellent PK profiles with a 72% oral bioavailability in beagle dogs. Compound 24 demonstrated overall favorable in vitro safety profiles with respect to CYP isoform and hERG inhibition. Finally, compound 24 led to significant regression of subcutaneous tumor generated by primary Ptch1-deficient medulloblastoma cells in SCID mouse. In conclusion, tetrahydropyrido[4,3-d]pyrimidine derivatives represent a novel set of Smo inhibitors that could potentially be utilized to treat medulloblastoma and other Hh pathway related malignancies.
Lu, Wenfeng,Liu, Yongqiang,Ma, Haikuo,Zheng, Jiyue,Tian, Sheng,Sun, Zhijian,Luo, Lusong,Li, Jiajun,Zhang, Hongjian,Yang, Zeng-Jie,Zhang, Xiaohu
p. 1980 - 1994
(2017/09/25)

2 - chloro - N - (4 - chloro - 3 - (2 - pyridyl) phenyl) - 4 - methyl sulphone phenyl benzamide preparation method
The invention discloses a preparation method of 2-chlorine-N-(4-chlorine-3-(2-pyridyl)phenyl)-4-methyl sulfone phenyl benzamide. The reaction formula is as shown in the specification. The method disclosed by the invention has the advantages that the opera
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Paragraph 0037-0040

(2017/08/31)

Vismodegib and wherein the intermediate preparation method
The invention provides a preparation method for vismodegib and an intermediate of vismodegib, in other words, a preparation method for 2-chloro-N-(4-chloro-3-(pyridin-2-yl)-phenyl)-4-(methylsulfonyl)benzamide and the intermediate. The method comprises: ta
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Paragraph 0119; 0120; 0121

(2016/10/09)

Meta-Selective CAr-H Nitration of Arenes through a Ru3(CO)12-Catalyzed Ortho-Metalation Strategy
The first example of transition metal-catalyzed meta-selective CAr-H nitration of arenes is described. With the use of Ru3(CO)12 as the catalyst and Cu(NO3)2·3H2O as the nitro source, a wide spectrum of arenes bearing diversified N-heterocycles or oximido as the directing groups were nitrated with meta-selectivity exclusively. Mechanism studies have demonstrated the formation of a new 18e-octahedral ruthenium species as a key ortho-CAr-H metalated intermediate, which may be responsible for the subsequent meta-selective electrophilic aromatic substitution (SEAr). Moreover, this approach provides a fast-track strategy for atom/step economical synthesis of many useful pharmaceutical molecules.
Fan, Zhoulong,Ni, Jiabin,Zhang, Ao
supporting information
p. 8470 - 8475
(2016/07/26)

Selective Hydrogenation of Halogenated Nitroaromatics to Haloanilines in Batch and Flow
The selective hydrogenation of functionalized nitroaromatics poses a major challenge from both academic as well as industrial viewpoints. As part of the CHEM21 initiative (www.chem21.eu), we are interested in highly selective, catalytic hydrogenations of halogenated nitroaromatics. Initially, the catalytic reduction of 1-iodo-4-nitrobenzene to 4-iodoaniline served as a model system to investigate commercial heterogeneous catalysts. After determining optimal hydrogenation conditions and profiling performances of the best catalysts, hydrogenations were transferred from batch to continuous flow. Finally, the optimized flow conditions were applied to transformations which represent important steps in the syntheses of the active pharmaceutical ingredients clofazimine and vismodegib.
Loos, Patrick,Alex, Hannes,Hassfeld, Jorma,Lovis, Kai,Platzek, Johannes,Steinfeldt, Norbert,Hübner, Sandra
p. 452 - 464
(2016/03/04)

Method for preparing Vismodegib
The invention provides a preparation method for vismodegib, and in other words, a preparation method for 2-chloro-N-(4-chloro-3-(pyridin-2-yl)-phenyl)-4-(methylsulfonyl)benzamide. The method comprises: firstly preparing an intermediate 2-(3-nitrophenyl)py
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Paragraph 0175-0177

(2017/04/28)

Manufacturing Development and Genotoxic Impurity Control Strategy of the Hedgehog Pathway Inhibitor Vismodegib
The development work toward the robust and efficient manufacturing process to vismodegib, the active pharmaceutical ingredient (API) in Erivedge, is described. The optimization of the four-stage manufacturing process was designed to produce the API with the required critical quality attributes: (1) the selective catalytic hydrogenation reduction of the nitro compound 3 to the corresponding aniline 4 while minimizing the formation of potential genotoxic (mutagenic) impurities; (2) the control of the polymorphic phase and multipoint specification for particle size distribution.
Angelaud, Remy,Reynolds, Mark,Venkatramani, Cadapakam,Savage, Scott,Trafelet, Huldreich,Landmesser, Thomas,Demel, Peter,Levis, Michael,Ruha, Olivier,Rueckert, Baerbel,Jaeggi, Heinz
p. 1509 - 1519
(2016/08/30)

Click reaction as a tool to combine pharmacophores: The case of Vismodegib
Abstract The design and the preparation of a small library of 1,4-diphenyl-1,2,3-triazole derivatives is reported, with the aim to obtain a new class of Hedgehog pathway inhibitors. The smoothened protein is part of the hedgehog signaling pathway that is
Christodoulou, Michael S.,Mori, Mattia,Pantano, Rebecca,Alfonsi, Romina,Infante, Paola,Botta, Maurizio,Damia, Giovanna,Ricci, Francesca,Sotiropoulou, Panagiota A.,Liekens, Sandra,Botta, Bruno,Passarella, Daniele
p. 938 - 943
(2015/06/08)

Directed meta-Selective Bromination of Arenes with Ruthenium Catalysts
A Ru-catalyzed direct C?H activation/meta-bromination of arenes bearing pyridyl, pyrimidyl, and pyrazolyl directing groups has been developed. A series of bromo aryl pyridines and pyrimidines have been synthesized, and further coupling reactions have also been demonstrated for a number of representative functionalized arenes. Preliminary mechanistic studies have revealed that this reaction may proceed through radical-mediated bromination when NBS is utilized as the bromine source. This type of transformation has opened up a new direction for the radical non-ipso functionalization of metal with regard to future C?H activation development that would allow the remote functionalization of aromatic systems.
Yu, Qingzhen,Hu, Le'An,Wang, Yue,Zheng, Shasha,Huang, Jianhui
p. 15284 - 15288
(2016/01/25)

A facile synthetic route for antineoplastic drug GDC-0449
In the current study a facile synthetic route for preparing antineoplastic drug GDC-0449 is investigated. Starting with pyridine-1-oxide and 1-iodo-3-nitrobenzene, the intermediate product 2-(2-chloro-5-nitrophenyl) pyridine was prepared by cross-coupling
Cao, Meng,Hu, Hua-You,Zhao, Hu-Cheng,Zhang, Xi-Quan,Gu, Hong-Mei,Yang, Ling,Cai, Jin,Wang, Peng,Hu, Bing,Ji, Min
p. 1408 - 1414
(2014/07/21)

HEDGEHOG ANTAGONISTS HAVING ZINC BINDING MOIETIES
The present invention provides compounds which antagonize hedgehog signaling and inhibit HDAC activity. The com-pounds can be used in methods of treating proliferative dis-eases and disorders such as cancer
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(2014/02/16)

PYRIDYL INHIBITORS OF HEDGEHOG SIGNALLING
The invention provides novel inhibitors of hedgehog signaling that are useful as s therapeutic agent for treating malignancies where the compounds have the general formula (I): where A, X, Y R1, R2, R3, R4, m and n are as described herein.
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Page/Page column 69; 80

(2009/11/29)

GDC-0449-A potent inhibitor of the hedgehog pathway
SAR for a wide variety of heterocyclic replacements for a benzimidazole led to the discovery of functionalized 2-pyridyl amides as novel inhibitors of the hedgehog pathway. The 2-pyridyl amides were optimized for potency, PK, and drug-like properties by modifications to the amide portion of the molecule resulting in 31 (GDC-0449). Amide 31 produced complete tumor regression at doses as low as 12.5 mg/kg BID in a medulloblastoma allograft mouse model that is wholly dependent on the Hh pathway for growth and is currently in human clinical trials, where it is initially being evaluated for the treatment of BCC.
Robarge, Kirk D.,Brunton, Shirley A.,Castanedo, Georgette M.,Cui, Yong,Dina, Michael S.,Goldsmith, Richard,Gould, Stephen E.,Guichert, Oivin,Gunzner, Janet L.,Halladay, Jason,Jia, Wei,Khojasteh, Cyrus,Koehler, Michael F.T.,Kotkow, Karen,La, Hank,LaLonde, Rebecca L.,Lau, Kevin,Lee, Leslie,Marshall, Derek,Marsters Jr., James C.,Murray, Lesley J.,Qian, Changgeng,Rubin, Lee L.,Salphati, Laurent,Stanley, Mark S.,Stibbard, John H.A.,Sutherlin, Daniel P.,Ubhayaker, Savita,Wang, Shumei,Wong, Susan,Xie, Minli
scheme or table
p. 5576 - 5581
(2010/04/05)

Pyridyl inhibitors of hedgehog signalling
The invention provides novel inhibitors of hedgehog signaling that are useful as a therapeutic agents for treating malignancies where the compounds have the general formula I: wherein A, X, Y R1, R2, R3, R4, m and n are as described herein.
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Page/Page column 74

(2010/10/20)