- Preparation method of vimodegil
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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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- Multicomponent Reductive Cross-Coupling of an Inorganic Sulfur Dioxide Surrogate: Straightforward Construction of Diversely Functionalized Sulfones
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Conventionally, sulfones are prepared by oxidation of sulfides with strong oxidants. Now, a multicomponent reductive cross-coupling involving an inorganic salt (sodium metabisulfite) for the straightforward construction of sulfones is disclosed. Both intramolecular and intermolecular reductive cross-couplings were comprehensively explored, and diverse sulfones were accessible from the corresponding alkyl and aryl halides. Intramolecular cyclic sulfones were systematically obtained from five- to twelve-membered rings. Naturally occurring aliphatic systems, such as steroids, saccharides, and amino acids, were highly compatible with the SO2-insertion reductive cross-coupling. Four clinically applied drug molecules, which include multiple heteroatoms and functional groups with active hydrogens, were successfully prepared via a late-stage SO2 insertion. Mechanistic studies show that alkyl radicals and sulfonyl radicals were both involved as intermediates in this transformation.
- Meng, Yingying,Wang, Ming,Jiang, Xuefeng
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supporting information
p. 1346 - 1353
(2019/12/11)
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- Sulfoxide and sulfone compounds, as well as selective synthesis method and application thereof
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The invention discloses a method for selectively synthesizing a sulfoxide compound shown as a formula (II) and a sulfone compound shown as a formula (III). In a reaction solvent, thioether (I) is usedas a reaction raw material and oxygen as an oxidation reagent, under the catalytic action of visible light and a photosensitive reagent; under the assistance of an additive, when a large-polarity proton-containing additive such as an acid and an alcohol or a solvent or an additive with excellent electron donating ability is used, a sulfoxide compound (II) is selectively generated; and when a small-polarity aprotic additive or a solvent is used, a sulfone compound (III) is selectively generated. The synthesis method has the advantages of easily available and cheap raw materials, simple reaction operation, mild reaction conditions, high yield and excellent functional group tolerance. According to the invention, synthesis and modification of some medicines are realized, and an efficient method for selectively constructing sulfoxide and sulfone compounds is provided for medicinal chemistry research.
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Paragraph 0049-0052; 0166-0169
(2019/12/02)
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- Aryl alkyl sulfone compound and reducing coupling method for constructing sulfone compounds
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The invention discloses an aryl alkyl sulfone compound shown as a formula (1) and a synthetic method thereof. The aryl alkyl sulfone compound is prepared by taking an aromatic iodide, an inorganic sulfur reagent and an alkyl bromide as reaction raw materials to carry out reacting in a solvent under action of alkali, a catalyst, a ligand, a reducing agent and an additive. According to the invention, an inorganic sulfur reagent is used as a sulfur source to construct the aryl alkyl sulfone compound in one step under catalysis and reduction conditions, so that the defect in synthesizing the arylalkyl sulfone compound by conventional oxidation of thioether is avoided. The aryl alkyl sulfone compound developed by the invention can be used for synthesizing aryl alkyl sulfone medicines.
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Paragraph 0387-0391
(2019/12/25)
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- Preparation methods of Vismodegib and intermediate of Vismodegib
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The invention provides preparation methods of Vismodegib and an intermediate of the Vismodegib, namely, preparation methods of 2-chloro-N-(4-chloro-3-(2-pyridinyl)phenyl)-4-(methylsulfonyl)benzamide and an intermediate of the 2-chloro-N-(4-chloro-3-(2-pyridinyl)phenyl)-4-(methylsulfonyl)benzamide. According to the preparation methods, the intermediate, namely 2-chloro-4-methylsulfonyl-N-(3-(2-pyridinyl)phenyl)benzamide is prepared firstly, and then the 2-chloro-N-(4-chloro-3-(2-pyridinyl)phenyl)-4-(methylsulfonyl)benzamide is prepared through a chlorination reaction. The preparation methods have the characteristics that the steps are short, operation is easy, starting materials are cheap and easy to obtain, no palladium reagent is used, the reaction condition has the low requirements for the anhydrous and oxygen-free condition, and the production cost can be effectively lowered.
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- Selective Late-Stage Oxygenation of Sulfides with Ground-State Oxygen by Uranyl Photocatalysis
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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
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p. 13499 - 13506
(2019/08/21)
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- A Pyridine–Pyridine Cross-Coupling Reaction via Dearomatized Radical Intermediates
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A pyridine–pyridine coupling reaction has been developed between pyridyl phosphonium salts and cyanopyridines using B2pin2 as an electron-transfer reagent. Complete regio- and cross-selectivity are observed when forming a range of valuable 2,4′-bipyridines. Phosphonium salts were found to be the only viable radical precursors in this process, and mechanistic studies indicate that the process does not proceed through a Minisci-type coupling involving a pyridyl radical. Instead, a radical–radical coupling process between a boryl phosphonium pyridyl radical and a boryl-stabilized cyanopyridine radical explains the C?C bond-forming step.
- Koniarczyk, J. Luke,Greenwood, Jacob W.,Alegre-Requena, Juan V.,Paton, Robert S.,McNally, Andrew
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supporting information
p. 14882 - 14886
(2019/11/05)
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- A [...] synthesis of intermediates method and application
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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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- Synthetic Path To Pharmaceutically Acceptable Vismodegib
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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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- Palladium-Catalyzed Thiomethylation via a Three-Component Cross-Coupling Strategy
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In this report, the combination of masked inorganic sulfur and dimethyl carbonate was designed to achieve thiomethylated cross coupling of aryl chlorides. Remarkably, this powerful strategy realized thiomethylation of nucleosides bearing unprotected ribose, chloride-containing pharmaceuticals with late-stage coupling, and herbicides possessing multiple heteroatoms and steric hindrance. Moreover, this protocol is practically amenable to multigram-scale synthesis with a lower catalysis loading and a higher yield.
- Wang, Ming,Qiao, Zongjun,Zhao, Jiaoyan,Jiang, Xuefeng
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p. 6193 - 6197
(2018/09/25)
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- Design, synthesis and biological evaluation of deuterated Vismodegib for improving pharmacokinetic properties
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Vismodegib is an oral and high selective hedgehog (Hh) inhibitor used for the treatment of basal cell carcinoma (BCC). In this work, analogs of Vismodegib with deuterium-for-hydrogen replacement at certain metabolically active sites were prepared and found to have a better pharmacokinetic properties in mice. In particular, deuterated compound SKLB-C2211 obviously altered the blood circulation behavior compared to its prototype, which was demonstrated by significantly prolonged blood circulation half-life time (t1/2) and increased AUC0→∞. These results suggested SKLB-C2211 had the potential to be a long-acting inhibitor against Hh signaling pathway, and laid the foundation for the further research of its druggability.
- Wang, Fangying,Jiang, Hongxia,Deng, Yufang,Yu, Jiang,Zhan, Miao,Zhao, Lifeng,Chen, Yuanwei
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p. 2399 - 2402
(2018/06/25)
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- Method for preparing erivedge by adopting microchannel reaction device
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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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- [...] and intermediate preparation method (by machine translation)
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The present invention provides [...] and intermediate preparation method, namely 2 - chloro - N - (4 - chloro - 3 - (2 - pyridyl) phenyl) - 4 - (methyl sulfonyl) benzamide and intermediate preparation method. The method of the invention is to 2 - chloro - 4 - P-methylsulfonyl-benzoic acid as the starting material for preparing the intermediate 2 - chloro - 4 --methylsulfonyl - N - (3 - (2 - pyridyl) phenyl) benzamide, then through chlorination reaction to prepare 2 - chloro - N - (4 - chloro - 3 - (2 - pyridyl) phenyl) - 4 - (methyl sulfonyl) benzamide. The invention relates to the preparation method has the simple operation, environment friendly, without the use of a palladium catalyst, high yield, purity and the like, and the raw materials are cheap and easily obtained, reaction conditions and the like to the nonaqueous low environmental requirement, can effectively reduce the production cost. (by machine translation)
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Paragraph 0063; 0064; 0065; 0066; 0067
(2017/07/20)
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- Synthesis method of vismodegib
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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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- Palladium-Catalyzed ortho-Selective C-H Chlorination of Benzamide Derivatives under Anodic Oxidation Conditions
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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
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p. 8716 - 8724
(2017/08/23)
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- Preparation method of vismodegib
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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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- 2 - chloro - N - (4 - chloro - 3 - (2 - pyridyl) phenyl) - 4 - methyl sulphone phenyl benzamide preparation method
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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 0041-0043
(2017/08/31)
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- Method for preparing Vismodegib
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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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- Manufacturing Development and Genotoxic Impurity Control Strategy of the Hedgehog Pathway Inhibitor Vismodegib
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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
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p. 1509 - 1519
(2016/08/30)
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- Vismodegib and wherein the intermediate preparation method
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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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- Meta-Selective CAr-H Nitration of Arenes through a Ru3(CO)12-Catalyzed Ortho-Metalation Strategy
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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
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supporting information
p. 8470 - 8475
(2016/07/26)
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- PROCESS FOR PREPARATION OF 2-CHLORO-N-(4-CHLORO-3-PYRIDIN-2-YLPHENYL)-4-METHYLSULFONYLBENZAMIDE SOLID FORMS
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The present invention relates to crystalline 2-Chloro-N-(4-chloro-3-pyridin-2-ylphenyl)-4-methylsulfonylbenzamide (I) designated as Form-SV and process for preparation thereof. The invention further relates to pharmaceutical compositions comprising crysta
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Paragraph 0102
(2016/03/19)
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- SALTS OF 2-CHLORO-N-(4-CHLORO-3-(PYRIDIN-2-YL)PHENYL)-4-(METHYLSULFONYL)BENZAMIDE
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A salt comprising compound of Formula (I) and at least one acid component (HA).
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Page/Page column 19
(2015/11/27)
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- Directed meta-Selective Bromination of Arenes with Ruthenium Catalysts
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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
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supporting information
p. 15284 - 15288
(2016/01/25)
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- A facile synthetic route for antineoplastic drug GDC-0449
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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
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p. 1408 - 1414
(2014/07/21)
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- PYRIDYL INHIBITORS OF HEDGEHOG SIGNALLING
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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 103
(2009/11/29)
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- Pyridyl inhibitors of hedgehog signalling
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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 80
(2010/10/20)
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