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Novel oriented synthesis method of voriconazole, medicinal salt and intermediate thereof

A voriconazole and directional synthesis technology, which is applied in the direction of pharmaceutical formulations, non-active ingredients of polymer compounds, medical preparations containing active ingredients, etc., can solve problems such as high cost, unfavorable environmental protection, and unsatisfactory directional synthesis selectivity

Inactive Publication Date: 2007-02-28
大道隆达(北京)医药科技发展有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Above-mentioned two kinds of preparation methods are compared, and document CN1076019 has adopted directional synthesis technology, and conversion rate and yield are higher than the method for document CN1026788 chiral column separation, and operation is also comparatively simple, but still has many deficiencies: use iodine in a large amount, Not only the cost is high, but also not conducive to environmental protection; the ratio of 2R, 3S / 2S, 3R isomers and their enantiomers 2R, 3R / 2S, 3S produced by the reaction is only about 9:1, and the selectivity of directional synthesis is still high. It is not ideal, and it still needs to be refined into salt to obtain pure 2R, 3S / 2S, 3R isomers

Method used

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  • Novel oriented synthesis method of voriconazole, medicinal salt and intermediate thereof
  • Novel oriented synthesis method of voriconazole, medicinal salt and intermediate thereof
  • Novel oriented synthesis method of voriconazole, medicinal salt and intermediate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Embodiment 1: the preparation of double 4-chloro-5-fluoro-6-ethyl pyrimidine zinc

[0030] Install a mechanical stirrer, a thermometer, a reflux condenser and a gas introduction device in a 5L dry three-necked flask. Add 150.g (2.2mol) of copper-containing 5% zinc-copper alloy powder and 2000ml of anhydrous tetrahydrofuran to it successively, feed nitrogen, add 147g of 4-chloro-5-fluoro-6-(1-bromoethyl)pyrimidine (0.5mol), stirring and heating to reflux, after the reaction is initiated, add dropwise a 500ml tetrahydrofuran solution containing 440g (1.5mol) of 4-chloro-5-fluoro-6-(1-bromoethyl)pyrimidine to control the reaction rate Let it flow back smoothly. After the reaction was complete, cool, filter, and concentrate the filtrate to dryness. The residue was crystallized in a petroleum ether / diethyl ether mixed solvent, filtered, and dried to obtain 398 g of the target product bis-4-chloro-5-fluoro-6-ethylpyrimidine zinc. Yield: 81%, it can be directly used in the f...

Embodiment 2

[0031] Example 2: (2R,3S / 2S,3R)-2-(2,4 difluorophenyl)-3-(4-chloro-5-fluoropyrimidin-6-yl)-1-(1H-1, Preparation of 2,4-triazol-1-yl)-2-butanol hydrochloride (Method A)

[0032]Install mechanical stirring, reflux condenser, dropping funnel and thermometer in a 5 L dry reaction flask. Add (R)-(+)-1,1'-bis-2-naphthol 143g (0.5mol), tetraisopropyl titanate 852g (3.0mol), bis-4-chloro-5-fluoro- 738g (1.5mol) of 6-ethylpyrimidine zinc and 2000ml of tetrahydrofuran were stirred for 1 hour, cooled to below 0°C, and 2H-(1,2,4-triazole)-2,4-difluoro Acetophenone (side chain) 558g (2.5mol) tetrahydrofuran solution 1000ml, make the reaction temperature not exceed 5 ℃. After the addition was complete, the reaction was continued at 0-5°C for 10 hours. After the reaction was completed, it was poured into an aqueous solution of acetic acid, and after stirring at room temperature for 10 minutes, the supernatant was poured out, and the solvent was evaporated under reduced pressure to recover...

Embodiment 3

[0033] Example 3: (2R,3S / 2S,3R)-2-(2,4 difluorophenyl)-3-(4-chloro-5-fluoropyrimidin-6-yl)-1-(1H-1, Preparation of 2,4-triazol-1-yl)-2-butanol hydrochloride (Method B)

[0034] Install mechanical stirring, reflux condenser, dropping funnel and thermometer in a 100ml dry reaction flask. Add (R)-(+)-5,5',6,6',7,7',8,8'-octahydro-1,1'-bis-2-naphthol 1.5g (0.005 mol), tetraisopropyl titanate 8.5g (0.03mol), bis-4-chloro-5-fluoro-6-ethylpyrimidine zinc 7.4g (0.015mol) and tetrahydrofuran 20ml, after stirring for 1 hour, cool to 0 Below ℃, add dropwise 10ml of tetrahydrofuran solution containing 5.6g (0.025mol) of 2H-(1,2,4-triazole)-2,4-difluoroacetophenone (side chain), so that the reaction temperature does not exceed 5 ℃. After the addition was completed, the reaction was continued at 0-5°C for 8 hours. After the reaction was completed, it was poured into an aqueous solution of acetic acid, and after stirring at room temperature for 10 minutes, the supernatant was poured out,...

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Abstract

The invention discloses a new-typed antibiotic drug and medical salt and preparing method of one new directional intermediate, which is characterized by the following: adopting directional ketone synthetic technology corresponding to metal organic compound; preparing key intermediate (2R,3S / 2S,3R)-2-(2,4 difluorobenzene-3-(4-chlorin-5-fluoxydin-6-radical)-1-(1H-1, 2, 4-ribavirin-1-radical)-2-butanol or salt; reducing; dechlorinating; detaching to obtain voltyokonoside.

Description

field of invention [0001] The present invention relates to (2R,3S)-2-(2,4 difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazole-1 A new preparation method of -yl)-2-butanol (voriconazole), medicinal salts and intermediates thereof. Background technique [0002] Voriconazole is a new type of broad-spectrum triazole antifungal drug, which can inhibit the demethylation of 14α-sterol mediated by fungal cytochrome P450, thereby inhibiting the synthesis of fungal ergosterol, and has high selectivity for fungal cytochrome P450 enzymes Cytochrome P450 enzymes in various mammals. Voriconazole inhibits yeast and kills some filamentous organic matter. It has a higher affinity for lanosterol 14α-demethylase of mold than yeast, which can completely block the synthesis of ergosterol and lead to cell death. It has excellent antibacterial activity against fluconazole-resistant Candida albicans, and its antibacterial activity against pathogenic yeast is higher than that of flucon...

Claims

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Application Information

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IPC IPC(8): C07D403/06A61K31/506A61K47/40A61P31/10C07D249/00C07D239/00
Inventor 周华明周英
Owner 大道隆达(北京)医药科技发展有限公司
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