- A new and efficient protocol for the synthesis of the key intermediate of palbociclib
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A new and efficient synthesis of 6-bromo-8-cyclopentyl-5-methyl-2-(methylsulfinyl)-pyrido[2,3-d]pyrimidin-7(8H)-one, a key intermediate of Palbociclib, starting from thiouracil was described. This protocol involved methylation, nucleophilic substitution, bromination, nucleophilic substitution, Heck reaction, ring closure, oxidation, and bromination to afford a key intermediate of Palbociclib with approximately 35% overall yield. The advantages of this developed synthetic strategy included improved overall yield, inexpensive starting materials, and readily controllable and cleaner reaction conditions.
- Li, Shuting,Yang, Wanfeng,Ji, Min,Cai, Jin,Chen, Junqing
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- A new route for the synthesis of Palbociclib
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Abstract: In this paper, a novel synthetic method for Palbociclib was reported. It was synthesized in eight steps from 2-(methylthio) pyrimidin-4-(3H)-one with approximately 10% overall yield. This protocol started material 2-(methylthio) pyrimidin-4-(3H)-one, involved nucleophilic substitution by thionyl chloride, bromination, nucleophilic substitution by cyclopentylamine, a one pot-two step method (Heck reaction, ring close sequence), oxidation and bromination, cross-coupling reaction, Heck reaction, aqueous workup to afford Palbociclib. This synthetic route used inexpensive raw material and reagents, involved readily controllable reaction conditions and reduced environmental hazards. Graphic abstract: Synthesis of Palbociclib, a small molecule CDK inhibitor, starting from 2-(methylthio) pyrimidin-4-(3H)-one by 8 steps reaction. This method afforded the Palbociclib in 10% yield. [Figure not available: see fulltext.].
- Li, Shu-ting,Chen, Jun-qing,Feng, Cheng-liang,Yang, Wan-feng,Ji, Min
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p. 3043 - 3051
(2019/10/19)
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- Synthesis method of 4-chloro-2-methylthiopyrimidine
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The invention belongs to the technical field of organic synthesis, in particular to a synthesis method of 4-chloro-2-methylthiopyrimidine. The method includes taking 2-thiouracil as a raw material, dimethyl sulfate as a methylation reagent, thionyl chloride and phosphorus oxychloride as a chlorination reagent, and synthesizing the 4-chloro-2-methylthiopyrimidine through methylation and chlorination.The dimethyl sulfate is taken as the methylation reagent to replace methyl bromide or methyl iodide, and thus the safety of the reaction is increased, and the cost is decreased; sodium hydroxide istaken as alkali to replace sodium methoxide or butyl lithium, and thus the safety of the reaction is increased, and the cost is reduced; toluene is taken as a reaction solvent, and thus the dosage ofthe chlorinated reagent is greatly reduced, the reaction safety is greatly improved, the cost is reduced, and the post-treatment operation is simplified; and the sulfoxide chloride and the phosphorusoxychloride are taken as the mixed chlorinating reagent, and thus the reaction yield is greatly improved.
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Paragraph 0029; 0030; 0031; 0032-0035; 0044-0047
(2019/06/30)
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- Synthesis of N,N-dialkyl-1-(2-alkylthiopyrimidin-4-yl)piperidin- 4-amines as potential heat shock protein inhibitors
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A new efficient method for synthesizing promising heat shock protein inhibitors, N,N-dialkyl- 1-(2-alkylthiopyrimidin-4-yl)piperidin-4-amines, by the reaction of 2-alkyl-4-chlorothiouracils with 4-(N-alkyl-N-methylamino)piperidines was developed. 2-Alkyl-4-chlorothiouracils were synthesized by alkylation of 2-thiouracil with alkyl iodides and subsequent treatment of the intermediates with POCl3. 4-(N-Alkyl-N-methylamino)piperidines were prepared by reductive amination of 1-(tert-butoxycarbonyl)-4-piperidinone with methylamine followed by treatment of the intermediate with the appropriate aldehydes.
- Aldobaev,Prezent,Zavarzin
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p. 2127 - 2130
(2019/01/08)
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- NOVEL IN-VIVO PROBE FOR REAL TIME LONGITUDINAL MONITORING OF INDUCIBLE NITRIC-OXIDE SYNTHASE IN LIVING CELLS AND ANIMALS
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The present disclosure relates to an in vivo fluorescent or radioactive probe represented by a compound of formula I which is capable of longitudinal imaging of inducible nitric oxide synthase (iNOS) expression in living cells and living animals on a real time basis. The probe of the present disclosure can exhibit specific and high affinity binding to the iNOS enzyme with reduced enzyme inhibitory property and also enables longitudinal monitoring of iNOS expression along with its activity or NO production in a same experimental subject throughout the progression of a physiological or disease process without employing separate subjects as controls and experimental. The present disclosure further provides a rapid and inexpensive real time method for visualizing iNOS expression and its activity in living cells and living animals precisely, conveniently and reversibly along with simultaneous in vivo imaging of its catalytic product, nitric oxide (NO) in live physiological settings.
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Paragraph 0075
(2018/06/06)
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- Design, synthesis, and activity of 2-imidazol-1-ylpyrimidine derived inducible nitric oxide synthase dimerization inhibitors
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By the screening of a combinatorial library for inhibitors of nitric oxide (NO) formation by the inducible isoform of nitric oxide synthase (iNOS) using a whole-cell assay, 2-(imidazol-1-yl)pyrimidines were identified. Compounds were found to inhibit the dimerization of iNOS monomers, thus preventing the formation of the dimeric, active form of the enzyme. Optimization led to the selection of the potent, selective, and orally available iNOS dimerization inhibitor, 21b, which significantly ameliorated adjuvant-induced arthritis in a rat model. Analysis of the crystal structure of the 21b-iNOS monomer complex provided a rationalization for both the SAR and the mechanism by which 21b blocks the formation of the protein-protein interaction present in the dimeric form of iNOS.
- Davey, David D.,Adler, Marc,Arnaiz, Damian,Eagen, Keith,Erickson, Shawn,Guilford, William,Kenrick, Margaret,Morrissey, Michael M.,Ohlmeyer, Mike,Pan, Gonghua,Paradkar, Vidyadhar M.,Parkinson, John,Polokoff, Mark,Saionz, Kurt,Santos, Cecile,Subramanyam, Babu,Vergona, Ron,Wei, Robert G.,Whitlow, Marc,Ye, Bin,Zhao, Zuchun,Devlin, James J.,Phillips, Gary
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p. 1146 - 1157
(2007/10/03)
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- The Tautomeric Equilibria of Thio Analogues of Nucleic Acid Bases. Part 1. 2-Thiouracil: Background, Preparation of Model Compounds, and Gas-phase Proton Affinities
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The preparation is reported of all four the monoalkyl derivatives of 2-thiouracil and four of the six possible dialkyl derivatives required as models for a study of the tautomeric equilibria by physical methods.Gas-phase proton affinities are determined using ion cyclotron resonance mass spectrometry, and are used to provide quantitative estimates of individual tautomer stabilities in the vapour state.These quantitative results agree well with qualitative deductions of predominant structures for the monoalkyl derivatives from i.r. spectroscopy.
- Katritzky, Alan R.,Baykut, Gokhan,Rachwal, Stanislaw,Szafran, Miroslaw,Caster, Kenneth C.,Eyler, John
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p. 1499 - 1506
(2007/10/02)
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