- -catalyzed arylfluorination of α-diazoketoesters for facile synthesis of α-aryl-α-fluoroketoesters
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Here we describe the Cp?Rh(iii)-catalyzed cascade arylfluorination reactions of α-diazoketoesters with arylboronic acids and N-fluorobenzenesulfonimide for one-pot C(sp3)-C(aryl) and C(sp3)-F bond formation. The arylfluorination reaction can be accomplished with remarkable chemo- and regioselectivity. Our mechanistic investigation showed that the Rh-catalyzed arylfluorination of diazoacetates occurred by (1) transmetalation of arylboronic acids to form an arylrhodium(iii) complex, (2) coupling of diazomalonates with the arylrhodium(iii) complex to form carbene-rhodium, (3) migratory carbene insertion to form a diketonato-rhodium(iii) complex-probably via rearrangement of the putative σ-alkylrhodium(iii) complex, and (4) electrophilic fluorination of the diketonato-rhodium to form the α-aryl-α-fluoromalonates.
- Ng, Fo-Ning,Chan, Chun-Ming,Li, Jianbin,Sun, Mingzi,Lu, Yin-Suo,Zhou, Zhongyuan,Huang, Bolong,Yu, Wing-Yiu
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- Improved and single-pot process for the synthesis of macitentan, an endothelin receptor antagonist, via lithium amide-mediated nucleophilic substitution
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Abstract: An improved, simple, efficient, and telescoped synthesis of macitentan, an endothelin receptor antagonist, starting from 5-(4-bromophenyl)-4,6-dichloropyrimidine in an overall yield of around 62% is described. Graphical abstract: [Figure not available: see fulltext.].
- Jagtap, Kunal M.,Niphade, Navnath C.,Gaikwad, Chandrashekhar T.,Shinde, Gorakshanath B.,Toche, Raghunath B.,Joshi, Divyesh R.,Mathad, Vijayavitthal T.
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p. 653 - 661
(2018/03/09)
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- Palladium-Catalyzed Asymmetric Allylic Alkylation of 4-Substituted Isoxazolidin-5-ones: Straightforward Access to β2,2-Amino Acids
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We report here an unprecedented and highly enantioselective palladium-catalyzed allylic alkylation applied to 4-substituted isoxazolidin-5-ones. Ultimately, the process provides a straightforward access to β2,2-amino acids bearing an all-carbon quaternary stereogenic center in great yields and a high degree of enantioselectivity.
- Nascimento de Oliveira, Marllon,Arseniyadis, Stellios,Cossy, Janine
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supporting information
p. 4810 - 4814
(2018/03/21)
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- Preparation method of 5-(4-bromophenyl)-4,6-dichloropyrimidine
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The invention belongs to the technical field of pharmaceutical chemistry synthesis, and relates to a preparation method of 5-(4-bromophenyl)-4,6-dichloropyrimidine. The preparation method comprises the following steps: carrying out catalytic esterification on bromophenylacetic acid to prepare methyl p-bromophenylacetate, then carrying out a reaction with dimethyl carbonate to synthesize 2-(4-bromophenyl)-malonic acid-1,3-diethyl ester, carrying out cyclization by using formamidine hydrochloride to obtain 5-(4-bromophenyl)-4,6-dihydroxy pyrimidine, and then carrying out chlorination to obtain the product 5-(4-bromophenyl)-4,6-dichloropyrimidine. In the preparation process of the intermediate 1, a solid acid is adopted as a catalyst, so that the synthesis process and a post-treatment step are simplified. The solid acid is easy to separate and can be repeatedly used, so that resources are saved, and production cost is reduced. In a process of preparing the intermediate 2, sodium methoxideis adopted as an alkali to replace sodium hydride or amino sodium used in the prior art, so that production safety is improved, and production cost is reduced. Meanwhile, the intermediate 3 is prepared by adopting a one-pot method, so that operation steps are reduced.
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Paragraph 0050; 0054; 0061; 0068; 0082; 0089
(2019/01/08)
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- AN IMPROVED PROCESS FOR THE PREPARATION OF MACITENTAN
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The present invention relates to an improved process for the preparation of macitentan and pharmaceutical acceptable salts thereof. Further present invention also relates to methylene chloride solvate of macitentan and their use in the preparation of pure macitentan.
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Page/Page column 18; 19; 20
(2017/09/07)
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- SUBSTITUTED BIPIPERIDINYL DERIVATIVES
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The invention relates to novel substituted bipiperidinyl derivatives, to processes for their preparation, to their use for the treatment and/or prevention of diseases and to their use for preparing medicaments for the treatment and/or prevention of diseases, in particular for the treatment and/or prevention of diabetic microangiopathies, diabetic ulcers on the extremities, in particular for promoting wound healing of diabetic foot ulcers, diabetic heart failure, diabetic coronary microvascular heart disorders, peripheral and cardiac vascular disorders, thromboembolic disorders and ischaemias, peripheral circulatory disturbances, Raynaud's phenomenon, CREST syndrome, microcirculatory disturbances, intermittent claudication, and peripheral and autonomous neuropathies.
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Paragraph 0611; 0612; 0613
(2016/11/17)
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- Gold(I)-Catalyzed Enantioselective Desymmetrization of 1,3-Diols through Intramolecular Hydroalkoxylation of Allenes
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A gold(I)-catalyzed enantioselective desymmetrization of 1,3-diols was achieved by intramolecular hydroalkoxylation of allenes. The catalyst system 3-F-dppe(AuCl)2 /(R)-C8-TRIPAg proved to be specifically efficient to promote the desymmetrizing cyclization of 2-aryl-1,3-diols, which have proven challenging substrates in previous reports. Multisubstituted tetrahydrofurans were prepared in good yield with good enantioselectivity and diastereoselectivity by this method.
- Zi, Weiwei,Toste, F. Dean
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supporting information
p. 14447 - 14451
(2016/01/25)
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- The discovery of N -[5-(4-bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy] ethoxy]-4-pyrimidinyl]- N ′-propylsulfamide (macitentan), an orally active, potent dual endothelin receptor antagonist
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Starting from the structure of bosentan (1), we embarked on a medicinal chemistry program aiming at the identification of novel potent dual endothelin receptor antagonists with high oral efficacy. This led to the discovery of a novel series of alkyl sulfamide substituted pyrimidines. Among these, compound 17 (macitentan, ACT-064992) emerged as particularly interesting as it is a potent inhibitor of ETA with significant affinity for the ET B receptor and shows excellent pharmacokinetic properties and high in vivo efficacy in hypertensive Dahl salt-sensitive rats. Compound 17 successfully completed a long-term phase III clinical trial for pulmonary arterial hypertension.
- Bolli, Martin H.,Boss, Christoph,Binkert, Christoph,Buchmann, Stephan,Bur, Daniel,Hess, Patrick,Iglarz, Marc,Meyer, Solange,Rein, Josiane,Rey, Markus,Treiber, Alexander,Clozel, Martine,Fischli, Walter,Weller, Thomas
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p. 7849 - 7861
(2012/10/29)
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- 4-PYRIMIDINESULFAMIDE DERIVATIVE
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The invention relates to the compound of structural formula (I) and the salts thereof. Said compound is useful as endothelin receptor antagonist. The invention further relates to a process for preparing said compound.
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Page/Page column 5
(2012/06/16)
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- 4-PYRIMIDINESULFAMIDE DERIVATIVE
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The invention relates to the compound of structural formula (I) and the salts thereof. Said compound is useful as endothelin receptor antagonist. The invention further relates to a process for preparing said compound.
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Page/Page column 12-13
(2009/04/25)
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- NOVEL SULFAMIDES
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The invention relates to novel sulfamic acid amides and their use as active ingredients in the preparation of pharmaceutical compositions. The invention also concerns related aspects including pharmaceutical compositions containing one or more of those compounds and especially their use as endothelin receptor antagonists.
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Page/Page column 18-19
(2010/11/30)
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- PYRIMIDINE-SULFAMIDES AND THEIR USE AS ENDOTHELIAN RECEPTOR ANTAGONIST
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The invention relates to novel sulfamic acid amides of General Formula (I) and their use as active ingredients in the preparation of pharmaceutical compositions. The invention also concerns related aspects including processes for the preparation of the compounds, pharmaceutical compositions containing one or more of those compounds and especially their use as endothelin receptor antagonists. [ADD FORMULA]
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- Cyclic imino derivatives and pharmaceutical compositions containing them
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The invention relates to cyclic imino compounds which have, inter alia, valuable pharmacological properties, especially inhibitory effects on cell aggregation, pharmaceutical compositions which contain these compounds and processes for preparing them.
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- Synthesis of the 3H-labelled 5-HT3 antagonist (RS-25259-197) at high specific activity
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The preparation of the title compound, a selective 5-HT3 antagonist with anti-emetic properties, is described. The key intermediate involved is 6-bromo-1,2-dihydronaphthoid acid (5), which was synthesized from 4-bromophenylacetic acid by Micheal addition, acid-induced ring cyclization, reduction and dehydration. Compound (5) was selected because it has two labelling sites to ensure high specific activity of the final product. Reduction of amide 6 with carrier-free tritium gas, followed by reduction of the amide functional group with BF3-OEt2 and intramolecular cyclization furnished the title compound having a specific activity of 70.4 Ci/mmol and >99% purity.
- Gong, Leyi,Pames, Howard
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p. 425 - 433
(2007/10/03)
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