- Preparation method of 6-ethyl-5-fluoro-4-chloropyrimidine
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The invention provides a preparation method of 6-ethyl-5-fluoro-4-chloropyrimidine. The preparation method comprises the following steps of: preparation of 6-ethyl-5-chloro-4-hydroxypyrimidine; preparation of 6-ethyl-5-fluoro-4-hydroxypyrimidine; and finally, acquisition of 6-ethyl-5-fluoro-4-chloropyrimidine. According to the invention, cheap alpha-chloropropionyl ethyl acetate or alpha-chloropropionyl methyl acetate is used as the raw material, after ring closing, potassium fluoride is used for fluorination, and finally thionyl chloride is used for chlorination so as to obtain the high yield6-ethyl-5-fluoro-4-chloropyrimidine, and the reaction steps are simple and easy to control, the method is suitable for industrial production, such that a more valuable synthesis route is provided forpreparation of aprepitant, good social benefits and economic benefits can be brought about, and the economic value potential is great.
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- Voriconazole and intermediate preparation method
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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.
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Paragraph 0013; 0030-0041
(2019/05/15)
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- A 4 - (1-bromo-ethyl) - 5-fluoro-6-chloro-pyrimidine synthesis method
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The invention discloses a method for synthesizing 4-(1-bromoethyl) -5-fluoro-6-chloropyrimidine. The synthesis method comprises the steps of reacting 2-fluoro-ethyl acetate which is inexpensive and readily available and is used as an initial material with propionyl chloride under basic conditions in a solvent to synthesize an intermediate product 2-fluoro propionyl ethyl acetate; then carrying out cyclization on 2-fluoro propionyl ethyl acetate and formamidine acetate as well as a base in a solvent to obtain a cyclized product; then chlorinating the cyclized product with a chlorinating reagent; and finally adding a brominating reagent and brominating the chlorinated product in the presence of an initiator to obtain 4-(1-bromoethyl) -5-fluoro-6-chloropyrimidine. The synthesis method disclosed by the invention has the advantages of simple process, available raw materials, high yield, safety and environmental protection, and is convenient to industrialize.
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Paragraph 0023; 0033; 0038; 0039
(2017/02/23)
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- INDOLE AND AZAINDOLE MODULATORS OF THE ALPHA 7 NACHR
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This invention relates to modulation of the α7 nicotinic acetylcholine receptor (nAChR) by a compound of formula (I) or a pharmaceutically acceptable salt thereof.
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Page/Page column 49
(2011/05/05)
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- PROCESS FOR THE PREPARATION OF VORICONAZOLE
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The present invention provides a process for preparation of racemic voriconazole in a single reaction vessel. The present invention also provides a process for preparation of voriconazole using racemic voriconazole and the process of making it therewith.
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Page/Page column 8
(2012/01/13)
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- PROCESS FOR THE PREPARATION OF VORICONAZOLE
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The present invention provides a process for preparation of racemic voriconazole in a single reaction vessel. The present invention also provides a process for preparation of voriconazole using racemic voriconazole and the process of making it therewith.
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Page/Page column 17-18
(2010/09/17)
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- PROCESS FOR THE PRODUCTION OF VORICONAZOLE
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A process for the preparation of voriconazole is described wherein alkylthio substituted pyrimidines are key intermediates. The alkylthio substituents render the pyrimidines particularly suitable for metal mediated addition to ketones. This is demonstrated in a cross-coupling reaction for the preparation of voriconazole.
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Page/Page column 3-4
(2009/04/25)
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- PROCESS FOR PREPARING VORICONAZOLE
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Optically pure voriconazole can be prepared in a high yield by a) subjecting 1-(2,4-difluorophenyl)-2(1H-1,2,4-triazol-1-yl)ethanone to Reformatsky-type coupling reaction with a substituted thiopyrimidine derivative to obtain a desired (2R,3S)/(2S,3R)-enantiomeric pair; b) removing the thiol derivative from the enantiomer to obtain racemic voriconazole; and c) isolating the racemic voriconazole by way of optical resolution using an optically active acid.
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Page/Page column 7; 9
(2009/04/25)
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- IMPROVED PROCESS FOR THE PREPARATION OF 2R, 3S-2-(2,4-DIFLUOROPHENYL)-3-(5-FLUOROPYRIMIDIN-4-YL)-1-(1H-1,2,4-TRIAZOL-1-YL) BUTAN-2-OL (VORICONAZOLE)
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The present invention relates to an improved process for the preparation of 2R, 3S-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl) butan-2-ol. It may be represented as Formula (I).
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Page/Page column 8
(2008/06/13)
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- Preparation of triazoles by organometallic addition to ketones and intermediates therefor
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A process for the preparation of a compound of the formula: or an acid addition or base salt thereof, wherein R is phenyl optionally substituted by 1 to 3 substituents each independently selected from halo and trifluoromethyl; R1 is C1-C6 alkyl; and “Het” is pyrimidinyl optionally substituted by 1 to 3 substituents each independently selected from C1-C4 alkyl, C1-C4 alkoxy, halo, oxo, benzyl and benzyloxy, comprising reacting a compound of the formula: with a compound of the formula wherein X is chloro, bromo or iodo, the reaction taking place in the presence of zinc; at least one of iodine or a Lewis acid; and an aprotic organic solvent: optionally further reacting the resulting compound with an acid or base to form the corresponding acid addition or base salt thereof.
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- Process development of voriconazole: A novel broad-spectrum triazole antifungal agent
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In the synthesis of (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoro-4-pyrimidinyl)-1-(1H-1,2,4-triazol-1- yl)-2-butanol (voriconazole), the relative stereochemistry is set in the addition of a 4-(1-metalloethyl)-5-fluoropyrimidine derivative to 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)-1-ethanone. The diastereo-control of this reaction has been examined by variation of pyrimidine substitution pattern and by changes in the metalation and reaction conditions. Excellent diastereoselection (12: 1) is obtained using an organozinc derivative of 6-(1-bromoethyl)-4-chloro-5-fluoropyrimidine. After removal of the chlorine from the pyrimidine ring, the absolute stereochemistry of voriconazole is established via a diastereomeric salt resolution process using (1R)-10-camphorsulfonic acid. Synthetic routes to the pyrimidine partner have also been evaluated. The initial six-step development route from 5-fluorouracil has been superseded by a four-step synthesis involving fluorination of methyl 3-oxopentanoate and cyclisation with formamidine acetate.
- Butters, Mike,Ebbs, Julie,Green, Stuart P.,MacRae, Julie,Morland, Matthew C.,Murtiashaw, Charles W.,Pettman, Alan J.
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- Novel antifungal 2-aryl-1-(1H-1,2,4-triazol-1-yl)butan-2-ol derivatives with high activity against Aspergillus fumigatus
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Replacement of one triazole ring of fluconazole with 4-pyridinyl leads to an increase in activity against Aspergillus fumigatus. Introduction of an α-methyl group has a marked additional beneficial effect. Investigation of pyridinyl and pyrimidinyl analogues resulted in the identification of 30 (UK-109,496), voriconazole) which has excellent potency against a broad range of fungal pathogens including A. fumigatus and Candida krusei.
- Dickinson, Roger P.,Bell, Andrew S.,Hitchcock, Christopher A.,Narayanaswami, Subramaniyan,Ray, Stephen J.,Richardson, Kenneth,Troke, Peter F.
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p. 2031 - 2036
(2007/10/03)
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- Triazole antifungal agents
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The invention provide antifungal compounds of the formula: STR1 and pharmaceutically acceptable salts thereof, wherein R is phenyl substituted by 1 to 3 substituents each independently selected from halo, --CF3 and --OCF3 ; R1 is C1 -C4 alkyl; R2 is H or C1 -C4 alkyl; X is CH or N; and Y is F or Cl.
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