188416-29-7

Usage

Uses

Used in Pharmaceutical Industry:
RaceMic Voriconazole is used as an antifungal agent for the treatment or prevention of aspergillosis and candidal infections. It is particularly effective against Candida albicans and Candida parapsilosis due to its antifungal activity. Voriconazole therapy is associated with transient, asymptomatic serum aminotransferase elevations and is a known cause of clinically apparent acute drug-induced liver injury.

References

1. Voriconazole (UK-109,496) inhibits the growth and alters the morphology of fluconazole-susceptible and -resistant Candida speciesBelanger, P., et al. 1997. Antimicrob. Agents Chemother. 41: 1840-1842. PMID: 92577762. In vitro activities of voriconazole (UK-109,496) and four other antifungal agents against 394 clinical isolates of Candida sppMarco, F., et al. 1998. Antimicrob. Agents Chemother. 42: 161-163. PMID: 94492783. In vitro activity of the new triazole voriconazole (UK-109,496) against opportunistic filamentous and dimorphic fungi and common and emerging yeast pathogensEspinel-Ingroff, A. 1998. J. Clin. Microbiol. 36: 198-202. PMID: 9431946

Upstream product

• 1474024-65-1 (R)-((R)-2-(2,4-difluorophenyl)oxiran-2-yl)(5-fluoropyrimidin-4-yl)methanol 
• 1474024-66-2 (R)-(2-(2,4-difluorophenyl)oxiran-2-yl)(5-fluoropyrimidin-4-yl)-methanone 
• 1474024-67-3 (R)-4-(1-(2-(2,4-difluorophenyl)oxirane-2-yl)vinyl)-5-fluoropyrimidine 
• 288-88-0 1,2,4-Triazole 
• 1474024-68-4 4-((S)-1-((R)-2-(2,4-difluorophenyl)oxirane-2-yl)ethyl)-5-fluoropyrimidine 
• 51336-94-8 2-chloro-1-(2,4-dichlorophenyl)ethanone 
• 137234-87-8 6-ethyl-5-fluoro-4-hydroxypyrimidine 
• 1237496-99-9 6-ethyl-5-fluoropyrimidin-4-yl methanesulfonate 
• 1237497-00-5 6-(1-bromoethyl)-5-fluoropyrimidin-4-yl methanesulfonate 
• 906451-64-7 1-(2,4-difluorophenyl)-2-(3,5-dibromo-1H-1,2,4-triazol-1-yl)ethanone 
• 188416-38-8 (2R,3S)-3-(6-chloro-5-fluoropyrimidin-4-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1 yl)butan-2-ol 
• 861718-85-6 3-chloro-2-(2,4-difluorophenyl)-2-(trimethylsilanyloxy)propionaldehyde 
• 188416-35-5 3-(6-chloro-5-fluoropyrimidin-4-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol 
• 137234-74-3 4-chloro-6-ethyl-5-fluoropyrimidine 

Downstream Products

• 194798-86-2 voriconazole phosphate 
• 1449785-88-9 2-(2,4-difluorophenyl)-1-(1H-1,2,4,-triazol-1-yl)ethen-2-ol 
• 1620283-06-8 C₁₉H₁₉F₂N₇O₅ 
• 1620283-09-1 C₂₄H₂₂F₃N₇O₆ 

Relevant academic research and scientific papers

Voriconazole synthesis process

The invention discloses a synthesis process of voriconazole bulk drug, which comprises the following steps: preparing halogenated ethyl fluorouracil and carrying out Grignard reaction. 2 - (2, 4 - Difluorophenyl) -3 - (1, 2, 4 - triazol -1 -yl) -1, 2 - propylene glycol was oxidized to give a propylene oxide compound. The Grignard reagent and the propylene oxide compound are mixed and reacted to obtain voriconazole. To the synthesis process, the reaction steps can be simplified, the dehydrochlorination and hydrogenolysis of palladium carbon are not needed, the reaction period is shortened, and furthermore, the energy consumption is reduced, the cost is reduced, and voriconazole and the racemate thereof are obtained with higher yield.

Voriconazole synthesis method

The invention relates to a voriconazole synthesis method, which comprises: 1, carrying out catalytic hydrogenation on an SM, anhydrous methanol and anhydrous sodium acetate reaction system by using palladium carbon; after treatment, crystallization is performed to obtain a voriconazole racemate; 2, the voriconazole racemate, an acetone solvent and an L(-)-camphor-10-sulfonic acid system are subjected to a reflux reaction, crystallization and filtration are performed after the reaction is completed, voriconazole camphorsulfonate is obtained, and the molar ratio of L-camphorsulfonic acid to thevoriconazole racemate is 0.5:1; and 3, adjusting the pH value of the voriconazole camphor sulfonate, dichloromethane and water system to 10-11 by using a sodium hydroxide aqueous solution, layering, and temporarily storing an organic phase; extracting the water phase with dichloromethane; and merging the organic phases, carrying out reduced pressure distillation to remove the solvent, and carryingout post-treatment to obtain voriconazole.

Improved voriconazole racemate preparation method

The invention relates to an improved voriconazole racemate preparation method. The method comprises the following steps: (1) reacting 2 '4'-difluoro-2-[1- (1H-1, 2, 4-triazolyl)] acetophenone with 4-(1-bromoethyl)-5-fluoro-6-chloropyrimidine in the presence of zinc powder, lead powder and iodine to prepare R, S/S and R-1; (2) in the presence of a palladium-carbon catalyst and under a heating condition, taking R, S/S, R-1 or a salt thereof as a reaction substrate to react with ammonium formate in a reaction solvent to prepare a voriconazole racemate reaction solution; and filtering the reactionsolution, collecting a filtrate, carrying out concentrating, adding water, adjusting the pH value of the solution to 7-9, stirring, filtering, collecting a filter cake, and drying to obtain the product; and (3) splitting the voriconazole racemate by using 1R-(-)- camphorsulfonic acid to prepare the voriconazole. According to the preparation method, alkali degradation is avoided, and impurities are reduced; meanwhile, the preparation method does not need to treat R, S/S and R-1 hydrochloride, direct reaction can be carried out, meanwhile, post-treatment does not need operations such as extraction, and the preparation method has the advantages of being simple and convenient to operate, safe, controllable, high in reproducibility, high in product yield, high in purity, low in cost, suitablefor industrial production and the like.

Synthesis method of voriconazole and intermediate of voriconazole

The invention relates to a synthesis method of voriconazole and an intermediate of voriconazole. The synthesis method comprises the following step: in a protective gas atmosphere, reacting a compoundshown in formula I and a compound shown in formula II in an organic solvent under the action of a metal catalyst, N-heterocyclic carbene, samarium diiodide and elemental iodine to obtain the voriconazole intermediate shown in formula III. According to the synthesis method of the voriconazole intermediate, under the action of the metal catalyst and SmI2, N-heterocyclic carbene is simultaneously added as a ligand, and elemental iodine is used as an initiator to initiate a reformask coupling reaction between the compound shown in formula I and the compound shown in formula II, so that the defectsof low yield, more byproducts and the like of the traditional reaction are overcome, and the yield and the purity are further improved.

Preparation method of voriconazole intermediate

The invention is suitable for the technical field of chemical synthesis and medicine, and provides a preparation method of voriconazole intermediate, which comprises steps of: carrying out a bromination reaction on 4-chloro-6-ethyl-fluoropyrimidine, N-bromosuccinimide, azodiisobutyronitrile and a first solvent to obtain a first intermediate; carrying out condensation reaction on the first intermediate, 2',4'-difluoro-2-[1-(1H-1,2,4-triazolyl)]acetophenone, zinc powder subjected to acid treatment and a second solvent to obtain a second intermediate; mixing the second intermediate, a third solvent and potassium formate to obtain a mixed solution; and adding palladium carbon into the mixed solution, and carrying out reflux reaction in a protective atmosphere to obtain the voriconazole intermediate. According to the preparation method disclosed by the invention, the voriconazole intermediate with high yield and high purity can be prepared.

Voriconazole and intermediate preparation method

The present invention discloses a Voriconazole condensate isomer as raw materials for recovery under acidic conditions to obtain 4 - chloro - 6 - ethyl - 5 - fluoro pyrimidine and 2 '4' - difluoro - 2 - [1 - (1 H - 1, 2, 4 - triazolyl)] acetophenone, and can further be used for the preparation of Voriconazole. The method can greatly improve the prior art for preparing the utilization rate of the fu likang zuozuo original auxiliary materials, the cost is reduced.

A process for the preparation of key intermediates of Voriconazole

The invention discloses a novel method for preparing a voriconazole key intermediate. The method comprises the following steps: catalyzing 1-(4-chloro-5-fluoropyridine-6-yl) halogenated ethane and 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazole-1-yl) ethanone by adopting a high-stereoselectivity chiral amino alcohol catalyst and a zinc-copper coupling agent, producing an asymmetric addition reaction to obtain (2R,3S/2S,3R)-2-(2,4-difluorophenyl)-3-(4-chloro-5-fluoropyridine-4-yl)-1-(1H-1,2,4-triazole-1-yl)-2-butanol, performing hydrogenation and dehalogenation to prepare a voriconazole key intermediate (2R,3S/2S,3R)-2-(2,4-difluorophenyl)-3-(5-fluoropyridine-4-yl)-1-(1H-1,2,4-triazole-1-yl)-2-butanol, and resolving to obtain the voriconazole. According to the method, the relatively economic and environment-friendly natural chiral amino alcohol catalyst is used; halogenated hydrocarbons and ketone are adopted to be subjected to the high-stereoselectivity asymmetric addition reaction, the process of preparing the halogenated hydrocarbons and active zinc into an organic zinc metal compound at first and then producing the asymmetric addition reaction between the compound and the ketone is removed, the operation is simplified, the production cost is reduced, and the industrialization is facilitated.

A preparation method of Voriconazole

The invention relates to a preparation method for voriconazole. The preparation method comprises the following steps: 1) a compound A is reacted with D-camphor-10-sulfonyl chloride as shown in the description to obtain a compound B; 2) the compound B is brominated to obtain a compound C; 3) the compound C and a compound 5 are subjected to condensation to obtain a compound 6; 4) the compound is subjected to palladium-carbon catalytic hydrogenation to obtain the voriconazole. According to the prepared method, the synthesis method is simple, the three-dimensional selectivity is high, raw materials are easy to obtain, and the cost is low.

Method for synthesizing voriconazole

The invention provides a method for synthesizing voriconazole, belonging to the field of medicine synthesis. The method comprises the following steps: by taking an intermediate A as a raw material, performing catalytic reaction with potassium formate and palladium-charcoal in the presence of inert gas so as to obtain a crude product of voriconazole, and recrystallizing the crude product of voriconazole, thereby obtaining voriconazole. According to the method, potassium formate is adopted as a hydrogen source and palladium-charcoal is adopted as a catalyst, helium atoms on pyrimidine rings of the intermediate A are removed, and thus raceme of voriconazole can be obtained. According to the method, the quantity of byproducts is few, the product quality is high, the reaction condition is gentle, the process security is high and the method is applicable to industrial large-scale production.

Preparation method of voriconazole

The invention discloses a preparation method of voriconazole, which includes the steps of: dissolving a compound B in a solvent, controlling the temperature of the reaction liquid to be -70 - 0 DEG C, stirring the reaction liquid, adding alkali with stirring and controlling the temperature of the reaction liquid to be -70 - 0 DEG C, stirring the reaction liquid, dropwise adding a mixed liquid of A and a solvent, and after the mixed liquid is added completely, controlling the temperature of the reaction liquid to be -70 - 0 DEG C to perform a reaction for 2-48 h to obtain the compound (1). In the process, a required chiral configuration is introduced from the raw material A, so that the method has high stereoselectivity and is free of chiral resolution in the subsequent steps. Qualified product can be produced only through a simple re-crystallization step, so that the method is suitable for industrial production.