6277-02-7Relevant academic research and scientific papers
Asymmetric Transfer Hydrogenation of α-Substituted-β-Keto Carbonitriles via Dynamic Kinetic Resolution
Wang, Fangyuan,Yang, Tilong,Wu, Ting,Zheng, Long-Sheng,Yin, Congcong,Shi, Yongjie,Ye, Xiang-Yu,Chen, Gen-Qiang,Zhang, Xumu
supporting information, p. 2477 - 2483 (2021/02/16)
A catalytic protocol for the enantio- and diastereoselective reduction of α-substituted-β-keto carbonitriles is described. The reaction involves a DKR-ATH process with the simultaneous construction of β-hydroxy carbonitrile scaffolds with two contiguous stereogenic centers. A wide range of α-substituted-β-keto carbonitriles were obtained in high yields (94%-98%) and excellent enantio- and diastereoselectivities (up to >99% ee, up to >99:1 dr). The origin of the diastereoselectivity was also rationalized by DFT calculations. Furthermore, this methodology offers rapid access to the pharmaceutical intermediates of Ipenoxazone and Tapentadol.
Preparation of 3,4-Substituted-5-Aminopyrazoles and 4-Substituted-2-Aminothiazoles
Havel, Stepan,Khirsariya, Prashant,Akavaram, Naresh,Paruch, Kamil,Carbain, Benoit
, p. 15380 - 15405 (2019/01/04)
3,4-Substituted-5-aminopyrazoles and 4-substituted-2-aminothiazoles are frequently used intermediates in medicinal chemistry and drug discovery projects. We report an expedient flexible synthesis of 3,4-substituted-5-aminopyrazoles (35 examples), based on palladium-mediated α-arylation of β-ketonitriles with aryl bromides. A library of 4-substituted-2-aminothiazoles (21 examples) was assembled by a sequence employing Suzuki coupling of newly prepared, properly protected pinacol ester and MIDA ester of 4-boronic acid-2-aminothiazole with (hetero)aryl halides.
BF3·OEt2-mediated [1,2]-aryl shift: Synthesis of functionalized α-arylnitriles via the bromination/cyanation/deformylation of substituted deoxybenzoin
Chan, Chieh-Kai,Chang, Meng-Yang
, p. 5207 - 5213 (2017/07/28)
A new sequential, tandem synthesis of functionalized α-arylnitriles via the bromination/cyanation/deformylation of substituted deoxybenzoin has developed. CuBr2-promoted bromination of substituted deoxybenzoins gives 2-bromo-2-arylacetophenne 3. The cyanation of 3 with sodium cyanide (NaCN) generates epoxynitrile. Then, a treatment of epoxynitrile with BF3·OEt2 results in the formation of functionalized α-arylnitriles 4 via a 1,2-aryl shift.
Synthesis and cytotoxic evaluation of some new 1-(6- chloropyridazin-3-Yl)-3-H/Alkyl-4-phenyl-1H-pyrazol- 5-amines and their derivatives
Mamta,Aggarwal, Ranjana,Smith, Jessie,Sadana, Rachna
, p. 59 - 68 (2019/01/18)
Synthesis of new 1-(6-chloropyridazin-3-yl)-3-H/alkyl-4-phenyl-1H-pyrazol-5-amines (3) was accomplished by the reaction of 3-chloro-6-hydrazinopyridazine (1) with differently substituted β-ketonitriles (2) under reflux in ethanol. Subsequently, a series of 6-amino derivatives (4, 5 and 6) was synthesized by amino-de-halogenation of 3 with secondry cyclic amines e.g. pyrrolidine, piperidine and morpholine respectively. Structures of all the compounds were established by IR, NMR (1H, 13C and 19F) and mass spectral data, and elemental analysis. All the compounds were screened for their cytotoxic effects against three cancer cell lines (SB-ALL, NALM-6, MCF-7) using colorimetric MTT assay.
Pyrimethamine Derivatives: Insight into Binding Mechanism and Improved Enhancement of Mutant β- N -acetylhexosaminidase Activity
Tropak, Michael B.,Zhang, Jianmin,Yonekawa, Sayuri,Rigat, Brigitte A.,Aulakh, Virender S.,Smith, Matthew R.,Hwang, Hee-Jong,Ciufolini, Marco A.,Mahuran, Don J.
, p. 4483 - 4493 (2015/06/23)
In order to identify structural features of pyrimethamine (5-(4-chlorophenyl)-6-ethylpyrimidine-2,4-diamine) that contribute to its inhibitory activity (IC50 value) and chaperoning efficacy toward β-N-acetylhexosaminidase, derivatives of the compound were synthesized that differ at the positions bearing the amino, ethyl, and chloro groups. Whereas the amino groups proved to be critical to its inhibitory activity, a variety of substitutions at the chloro position only increased its IC50 by 2-3-fold. Replacing the ethyl group at the 6-position with butyl or methyl groups increased IC50 more than 10-fold. Surprisingly, despite its higher IC50, a derivative lacking the chlorine atom in the para-position was found to enhance enzyme activity in live patient cells a further 25% at concentrations >100 μM, while showing less toxicity. These findings demonstrate the importance of the phenyl group in modulating the chaperoning efficacy and toxicity profile of the derivatives.
Ametoctradin is a Potent Qo Site Inhibitor of the Mitochondrial Respiration Complex III
Zhu, Xiaolei,Zhang, Mengmeng,Liu, Jingjing,Ge, Jingming,Yang, Guangfu
, p. 3377 - 3386 (2015/04/14)
Ametoctradin is a new Oomycete-specific fungicide under development by BASF. It is a potent inhibitor of the bc1 complex in mitochondrial respiration. However, its detailed action mechanism remains unknown. In the present work, the binding mode of ametoctradin was first uncovered by integrating molecular docking, MD simulations, and MM/PBSA calculations, which showed that ametoctradin should be a Qo site inhibitor of bc1 complex. Subsequently, a series of new 1,2,4-triazolo[1,5-a]pyrimidine derivatives were designed and synthesized to further understand the substituent effects on the 5- and 6-position of 1,2,4-triazolo[1,5-a]pyrimidine. The calculated binding free energies (ΔGcal) of newly synthesized analogues as Qo site inhibitors correlated very well (R2 = 0.96) with their experimental binding free energies (ΔGexp). Two compounds (4a and 4c) with higher inhibitory activity against porcine SQR than ametoctradin were successfully identified. The structural and mechanistic insights obtained from the present study will provide a valuable clue for future designing of a new promising bc1 inhibitor.
HETEROCYCLIC COMPOUNDS FOR THE INHIBITION OF PASK
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Page/Page column 37, (2012/11/08)
Disclosed herein are new heterocyclic compounds and compositions and their application as pharmaceuticals for the treatment of disease. Methods of inhibiting PAS Kinase (PASK) activity in a human or animal subject are also provided for the treatment of diseases such as diabetes mellitus.
COMPOUNDS FOR THE TREATMENT OF LYSOSOMAL STORAGE DISEASES
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Page/Page column 14; 15, (2011/08/22)
A method of treating a lysosomal storage disease comprises administering a pyrimethamine derivative to a subject in need thereof.
A high-yielding preparation of β-ketonitriles
Ji, Yaohui,Trenkle, William C.,Vowles, James V.
, p. 1161 - 1163 (2007/10/03)
β-Ketonitriles are important precursors for a wide variety of biologically active heterocycles. A facile procedure for the high-yielding acylation of nitrite anions with unactivated esters to provide β-ketonitriles is reported. The procedure is successful with enolizable and nonenolizable esters as well as hindered nitrile anions.
An expeditious synthesis of 6-alkyl-5-(4′ -amino-phenyl)-pyrimidine-2,4-diamines
Holsworth, Daniel D.,Stier, Michael,Edmunds, Jeremy J.,He, Wei,Place, Samuel,Maiti, Samarendra
, p. 3467 - 3475 (2007/10/03)
A rapid synthesis of a series of 6-alkyl substituted-5-(4′ -amino-phenyl)-pyrimidine-2,4-diamines is described. These analogs were produced in good yields on moderate scale (ca. 8 g) without chromatography. Furthermore, the methodology described herein al
