35150-07-3Relevant articles and documents
Synthetic Studies on Alotamide A: Construction of N-Demethylalotamide A
Domínguez, Marta,Román, David,Souto, José A.,de Lera, ángel R.
supporting information, p. 6057 - 6070 (2021/12/10)
Several approaches to the synthesis of cyclodepsipeptide natural product alotamide A are described, eventually affording a very advanced N-demethylated analogue of the targeted natural product. The difficulties found in our endeavors on the synthesis of alotamide A have allowed us to gather some valuable information regarding the most convenient synthetic step for each key transformation. The intramolecular Csp2?Csp2 Stille cross-coupling and the macrolactam formation were found to be reliable protocols for the final construction of the alotamide A skeleton.
Process Development of a Copper(II)-Catalyzed Dehydration of an N -Acyl Prolinal Oxime: Cascade Process and Application at an Elevated Lab Scale
Nonnhoff, Jannis,Gr?ger, Harald
supporting information, p. 4672 - 4677 (2021/10/07)
Chiral N-acyl amino nitriles are important structural motifs in several pharmaceuticals such as Vildagliptin or Saxagliptin. Cyanidefree access to such nitriles is provided by a copper-catalyzed dehydration of oximes, which are readily available by condensation of chiral aldehydes resulting from the chiral pool with hydroxylamine. The application in a cascade process without the need for intermediate purification as well as a demonstrated scalability show the robustness of this methodology.
Process Development of the Copper(II)-Catalyzed Dehydration of a Chiral Aldoxime and Rational Selection of the Co-Substrate
Gr?ger, Harald,Nonnhoff, Jannis
, (2021/12/14)
The access towards chiral nitriles remains crucial in the synthesis of several pharmaceuticals. One approach is based on metal-catalyzed dehydration of chiral aldoximes, which are generated from chiral pool-derived aldehydes as substrates, and the use of a cheap and readily available nitrile as co-substrate and water acceptor. Dehydration of N-acyl α-amino aldoximes such as N-Boc-l-prolinal oxime catalyzed by copper(II) acetate provides access to the corresponding N-acyl α-amino nitriles, which are substructures of the pharmaceuticals Vildagliptin and Saxagliptin. In this work, a detailed investigation of the formation of the amide as a by-product at higher substrate loadings is performed. The amide formation depends on the electronic properties of the nitrile co-substrate. We could identify an acceptor nitrile which completely suppressed amide formation at high substrate loadings of 0.5 m even when being used with only 2 equivalents. In detail, utilization of trichloroacetonitrile as such an acceptor nitrile enabled the synthesis of N-Boc-cyanopyrrolidine in a high yield of 92 % and with full retention of the absolute configuration.
(S)-4/5-phenyl-2-(pyrrolidin-2-yl)thiazole TRPV1 antagonists as well as preparation and application thereof
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Paragraph 0050; 0124; 0126-0127, (2020/07/28)
The invention discloses (S)-4/5-phenyl-2-(pyrrolidin-2-yl)thiazole novel TRPV1 antagonists as well as a preparation method and application thereof, and particularly relates to compounds represented bya general formula (I) or a general formula (II) and a pharmaceutically acceptable salt thereof. The compound have a strong analgesic effect, the activity of part of the compounds is far higher than that of a TRPV1 receptor antagonist BCTC, almost no body temperature rise side effect exists, and the invention further relates to a preparation method of the compounds and pharmaceutical preparationscontaining the compounds.
Evidence and exploitation of dicationic ammonium-nitrilium superelectrophiles: direct synthesis of unsaturated piperidinones
Cantin, Thomas,Morgenstern, Yvonne,Mingot, Agnès,Kornath, Andreas,Thibaudeau, Sébastien
supporting information, p. 11110 - 11113 (2020/10/05)
Exploiting superacid activation, the reactivity of aminonitriles was enhanced through the transient formation of highly reactive ammonium-nitrilium superelectrophiles. Demonstrated by usingin situlow-temperature NMR experiments and confirmed by X-ray diffraction analysis, these dications can be intramolecularly trapped by non-activated alkenes to generate unsaturated piperidinones, including enantioenriched ones, in a straightforward way.
Synthesis method of vildagliptin intermediate
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Paragraph 0031-0032; 0034-0035; 0037-0038; 0040-0041, (2020/12/15)
The invention discloses a synthesis method of a vildagliptin intermediate, and belongs to the technical field of organic synthesis. The method comprises the steps: reacting L-prolinamide serving as aninitial raw material with di-tert-butyl dicarbonate in the presence of a quaternary ammonium salt catalyst and potassium carbonate to obtain N-Boc-L-prolinamide, dehydrating and cyaniding the N-Boc-L-prolinamide and cyanuric chloride in a pure DMF system, adding acid carbonate and anhydrous sulfate, removing a solvent thoroughly, washing, adding p-toluenesulfonic acid, deprotecting, salifying, crystallizing, and obtaining (S)-pyrrolidine-2-carbonitrile p-toluenesulfonate; and finally, carrying out chloroacetylation reaction on the (S)-pyrrolidine-2-carbonitrile p-toluenesulfonate, and crystallizing by using a weak polar solvent to obtain (s)-1-(2-chloracetyl)pyrrolidine-2-carbonitrile. According to the method disclosed by the invention, the generation of impurities is reduced, the productyield loss caused by impurity treatment in the subsequent crystallization process is avoided, and the yield is as high as 80.6%; the purity reaches up to 99.7%; and the whole process is mild in reaction condition, stable in process material and suitable for industrial amplification.
Synthesis and Hypoglycemic Activity of Aryl(Hetaryl)Propenoic Cyanopyrrolidine Amides
Kuranov,Blokhin,Borisov,Khvostov,Luzina,Salakhutdinov
, p. 374 - 380 (2019/10/28)
Abstract: A series of amides based on (2S)-cyanopyrrolidine and α, β-unsaturated aryl- and hetarylcarboxylic acids have been synthesized. The dependence of the hypoglycemic activity of compounds on the structure of the aromatic fragment has been studied in the oral glucose tolerance test in mice. Amides based on (E)-3-phenylprop-2-enoic and (E)-3-(4-methoxyphenyl)prop-2-enoic acids and (2S)-cyanopyrrolidine have been shown to significantly reduce blood glucose levels in mice. The observed hypoglycemic effect at a dose of 10 mg/kg is comparable to the effect of hypoglycemic drug vildagliptin.
MODULATORS OF PROTEOLYSIS AND ASSOCIATED METHODS OF USE
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Paragraph 00619-00620, (2019/10/29)
The present disclosure relates to bifunctional compounds, which find utility as modulators of Kirsten rat sarcoma protein (target protein). In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a Von Hippel-Lindau, cereblon, Inhibitors of Apotosis Proteins or mouse double-minute homolog 2 ligand which binds to the respective E3 ubiquitin ligase and on the other end a moiety which binds the target protein, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aggregation, accumulation, and/or overactivation of the target protein are treated or prevented with compounds and compositions of the present disclosure.
Evaluation of Amino Nitriles and an Amino Imidate as Organo?-catalysts in Aldol Reactions
Brown, Alexander J.,Clarke, Paul A.,Vagkidis, Nikolaos
, p. 4106 - 4112 (2019/10/28)
The efficiency of l -valine and l -proline nitriles and a tert -butyl?- l -proline imidate as organocatalysts for the aldol reaction have been evaluated. l -Valine nitrile was found to be a syn -selective catalyst, while l -proline nitrile was found to be anti -selective, and gave products in modest to good enantioselectivities. tert -Butyl l -proline imidate was found to be a very efficient catalyst in terms of conversion of starting reagents to products, and gave good anti -selectivity. The enantioselectivity of the tert -butyl l -proline imidate was found to be good to excellent, with products being formed in up to 94percent enantiomeric excess.
A Potent, Selective, and Orally Bioavailable HCV NS5A Inhibitor for Treatment of Hepatitis C Virus: (S)-1-((R)-2-(Cyclopropanecarboxamido)-2-phenylacetyl)-N-(4-phenylthiazol-2-yl)pyrrolidine-2-carboxamide
Kang, Iou-Jiun,Hsu, Sheng-Ju,Yang, Hui-Yun,Yeh, Teng-Kuang,Lee, Chung-Chi,Lee, Yen-Chun,Tian, Ya-Wen,Song, Jen-Shin,Hsu, Tsu-An,Chao, Yu-Sheng,Yueh, Andrew,Chern, Jyh-Haur
, p. 228 - 247 (2017/04/26)
Starting from the initial lead 4-phenylthiazole 18, a modest HCV inhibitor (EC50 = 9440 nM), a series of structurally related thiazole derivatives has been identified as a novel chemical class of potent and selective HCV NS5A inhibitors. The introduction of a carboxamide group between the thiazole and pyrrolidine ring (42) of compound 18 resulted in a dramatic increase in activity (EC50 = 0.92 nM). However, 42 showed only moderate pharmacokinetic properties and limited oral bioavalability of 18.7% in rats. Further optimization of the substituents at the 4-position of the thiazole ring and pyrrolidine nitrogen of the lead compound 42 led to the identification of compound 57, a highly potent and selective NS5A inhibitor of HCV (EC50 = 4.6 nM), with greater therapeutic index (CC50/EC50 > 10000). Pharmacokinetic studies revealed that compound 57 had a superior oral exposure and desired bioavailability of 45% after oral administration in rats.
