- An Efficient Second-Generation Manufacturing Process for the pan-RAF Inhibitor Belvarafenib
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Herein, the development of a streamlined manufacturing process for the pan-RAF inhibitor belvarafenib (GDC-5573) is reported. The process to belvarafenib features a number of efficient key reactions, including a robust and scalable Pd-catalyzed carbonylation reaction to generate thienopyrimidine 2 and a highly chemoselective Pt/V/C-catalyzed nitro group reduction to access the penultimate intermediate 3. The final amide coupling was accomplished by a mild and safe protocol employing N,N,N′,N′-tetramethylchloroformamidinium hexafluorophosphate as the coupling reagent, which afforded belvarafenib on a multikilogram production scale after recrystallization.
- Zell, Daniel,Dalziel, Michael E.,Carrera, Diane E.,Stumpf, Andreas,Bachmann, Stephan,Mercado-Marin, Eduardo,Koenig, Stefan G.,Zhang, Haiming,Gosselin, Francis
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supporting information
p. 2338 - 2350
(2021/09/28)
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- O-dichlorobenzene with a quinolone drugs for coproduction method of key intermediate
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The invention relates to the field of methods for preparing medicinal intermediates, in particular to the field of methods for preparing key intermediates of quinolone medicines, and develops a method for coproducing the key intermediates of the quinolone medicines by using o-dichlorobenzene as a raw material. The method comprises the following steps of: nitrifying the o-dichlorobenzene serving as the raw material, and performing distillation, purification and stepwise crystallization to obtain 2,3-dichloronitrobenzene and 3,4-dichloronitrobenzene; performing fluoridation on the 2,3-dichloronitrobenzene to obtain 3-chloro-2-fluoronitrobenzene, performing chlorination to obtain 2,6-dichlorofluorobenzene, performing nitration to obtain 1,3-dichloro-2-fluoro-4-nitrobenzene, and finally performing fluoridation to obtain 2,3,4-trifluoronitrobenzene; and performing fluoridation on the 2,3,4-trifluoronitrobenzene to obtain 3-chloro-4-fluoronitrobenzene, performing chlorination to obtain 1,3-dichloro-4-fluorobenzene, and finally performing acylation reaction on the 1,3-dichloro-4-fluorobenzene and acetylchloride to obtain 2,4-dichloro-5-fluoroacetophenone.
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- Design, synthesis, SAR, and biological evaluation of highly potent benzimidazole-spaced phosphono-α-amino acid competitive NMDA antagonists of the AP-6 type
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A series of 2-amino-(phosphonoalkyl)-1H-benzimidazole-2-alkanoic acids was synthesized and evaluated for NMDA receptor affinity using a [3H]CPP binding assay. Functional antagonism of the NMDA receptor complex was evaluated in vitro using a stimulated [3H]TCP binding assay and in vivo by employing an NMDA-induced seizure model. Several compounds of the AP-6 type demonstrated potent and selective NMDA antagonistic activity both in vitro and in vivo. In particular, [R(-)]-2-amino-3-(5-chloro-1-phosphonomethyl-1H-benzoimidazol-2-yl)-propionic acid (1) displayed an IC50 value of 7.1 nM in the [3H]CPP binding assay and an ED50 value of 0.13 mg/kg (ip) in the NMDA lethality model. Compound 1, when administered intravenously as a single bolus dose of 3 mg/kg following permanent occlusion of the middle cerebral artery in the rat, reduced the volume of infarcted brain tissue by 45%. These results support a promising therapeutic potential for compound 1 as a neuroprotective agent.
- Baudy,Fletcher III,Yardley,Zaleska,Bramlett,Tasse,Kowal,Katz,Moyer,Abou-Gharbia
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p. 1516 - 1529
(2007/10/03)
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- Process for the preparation of chlorofluronitrobenzenes and difluoronitrobenzenes
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A process for the preparation of chlorofluoronitrobenzenes and difluoronitrobenzenes, which comprises heating dichloronitrobenzene to not more than 200° C. in excess with an alkali metal fluoride having a total water content of about 0.2 to about 2.5% by weight in the presence of a quaternary ammonium and/or phosphonium salt, crown ether and/or polyethylene glycol dimethyl ether as catalyst in the absence of a solvent.
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- Process for preparing fluoronitrobenzenes
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Fluoronitrobenzenes are prepared in an advantageous way from the corresponding chloronitrobenzenes and an alkali metal fluoride by means of a chlorine-fluorine exchange reaction with replacement of a chlorine atom by a fluorine atom, by catalyzing the reaction with a quaternaryammonium compound which comprises at least one alkoxypolyoxyalkyl radical.
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- Process for the synthesis of fluorinated derivatives
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A process for the synthesis of fluorinated organic compounds and a reagent suitable for use in the process. The process is carried out by exchange with fluorides, while preferably agitating the reaction medium with ultrasonic sound.
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- Preparation of fluoroaromatic compounds in dispersion of potassium fluoride
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An improved process is disclosed for preparing fluoroaromatic compounds (such as fluoronitrobenzene compounds) wherein chloroaromatic compounds (such as chloronitrobenzene compounds) are reacted with potassium fluoride in a solvent dispersion thereof prepared from a mixture including the solvent, the fluoride, methanol and an aromatic compound.
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- 4 AND 5-Halo substituted 2-indanamine compounds
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2-Indanamine compounds having 4 and 5-halo substituents are inhibitors of phenylethanolamine N-methyltransferase.
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