- Practical synthetic method for functionalized 1-methyl-3/5-(trifluoromethyl)-1H-pyrazoles
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A new, high-yielding, and practical method for synthesis of 1-methyl-3-(trifluoromethyl)-1H-pyrazole and 1-methyl- 5-(trifluoromethyl)-1H-pyrazole, key intermediates for important building blocks relevant to medicinal and agrochemistry, is developed. A one-step procedure for synthesis of the regioisomeric mixture of target pyrazoles was proposed starting from 4-ethoxy- 1,1,1-trifluoro-3-buten-2-one. The procedure for separation of this mixture was elaborated on the basis of the boiling point vs pressure diagram analysis. The efficient synthetic strategies for regioisomeric building blocks bearing CF3 groups at the 3rd and 5th positions were demonstrated. A set of 1-methyl-3-(trifluoromethyl)-1H-pyrazoles containing such a functional group as aldehyde, acid, boron pinacolate, lithium sulfinate, and sulfonyl chloride was synthesized based on lithiation of 1-methyl-3-(trifluoromethyl)- 1H-pyrazole in a flow reactor. Bromination of both 1-methyl-3-(trifluoromethyl)-1H-pyrazole and 1-methyl-5-(trifluoromethyl)-1Hpyrazole by NBS in mild conditions was performed. The introduction of the functional group at the 4th position of 1-methyl-5- (trifluoromethyl)-1H-pyrazole was illustrated by the optimized synthesis of the corresponding aldehyde and acid based on the Br-Li exchange in an appropriate bromide. Alternatively, the introduction of the functional group (acid and boron pinacolate) at the 5th position of 1-methyl-5-(trifluoromethyl)-1H-pyrazole was performed based on the direct ortho-metalation (DoM) reaction of 4- bromo-1-methyl-5-(trifluoromethyl)pyrazole followed by catalytic reductive debromination.
- Tairov, Maxim A.,Levchenko, Vitalina,Stadniy, Ivan A.,Dmytriv, Yurii V.,Dehtiarov, Serhii O.,Kibalnyi, Mykola O.,Melnyk, Anton V.,Veselovych, Stanislav Y.,Borodulin, Yurii V.,Kolotilov, Sergey V.,Ryabukhin, Sergey V.,Volochnyuk, Dmitriy M.
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p. 2619 - 2632
(2020/12/29)
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- Method for preparing heterocyclic small molecule compound
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The invention belongs to the field of medical chemistry, particularly belongs to the field of organic synthesis in medical chemistry, and more particularly relates to a preparation method of a heterocyclic small molecule compound. According to the preparation method, vinyl ethyl ether is used as a raw material, and a target compound, trifluoromethylpyrazole borate, is obtained through four steps.The product is an important building block in drug research, development and synthesis, and the industrial preparation method of the product can provide guarantee for subsequent in-depth research anddevelopment. Therefore, the invention is beneficial to research and development of related drug synthesis.
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Paragraph 0051; 0052; 0055; 0058
(2019/10/01)
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- 4-Methylsulfonyl-Substituted Piperidine Urea Compounds
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The present invention provides novel 4-methylsulphone-substituted piperidine urea compounds that are useful for the treatment of dilated cardiomyopathy (DCM) and conditions associated with left and/or right ventricular systolic dysfunction or systolic reserve. The synthesis and characterization of the compounds is described, as well as methods for treating DCM and other forms of heart disease.
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Paragraph 0162-0163
(2016/09/26)
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- Switchable reactivity: The site-selective functionalization of trifluoromethyl-substituted pyrazoles
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Modern organometallic methods enable the regioflexible conversion of simple heterocyclic starting materials into families of isomers and congeners. Depending on the choice of the reagent, 1-methyl-5-(trifluoromethyl)pyrazole (1) undergoes deprotonation and subsequent carboxylation mainly or exclusively at either the 4-position of the heterocycle or at the nitrogen-attached methyl group. Similarly, 1-phenyl-5-(trifluoromethyl)pyrazole (5) and 3-methyl-l-phenyl-5-(trifluoromethyl)pyrazole (8) are selectively attacked by lithium diisopropylamide at the heterocyclic 4-position and by butyllithium concomitantly at the 4-position and the ortho position of the phenyl ring. In contrast, metalation of 1-methyl-3-(trifluoromethyl)pyrazole (2) occurs only at the 5-position, whatever the organometallic or metal amide base. Further sites become accessible to functionalization if bromine is introduced into the heterocyclic or aromatic ring. This has been demonstrated with 4-bromo-1-methyl-5-(trifluoromethyl)pyrazole (3), 4-bromo-l-methyl-3-(trifluoromethyl)pyrazole (4), 4-bromo-1-methyl-5-(trifluoromethyl)pyrazole (7) and 1-(2-bromophenyl)-5-(trifluoromethyl)pyrazole (6). Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002.
- Schlosser, Manfred,Volle, Jean-Noel,Leroux, Frederic,Schenk, Kurt
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p. 2913 - 2920
(2007/10/03)
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