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Synthetic method of isavuconazole intermediate

A synthetic method, the technology of isavuconazole, which is applied in the field of synthesis of pharmaceutical intermediates, can solve the problems of being unsuitable for large-scale industrial production, low product yield, and high cost, and achieve low cost, good product purity, and high synthetic yield. Effect

Inactive Publication Date: 2016-03-23
黄燕鸽
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] In the prior art, the synthesis process of isavuconazole intermediates is often more complicated, the cost is higher, and there are also defects of low product yield and poor quality, which cannot be suitable for industrialized large-scale production

Method used

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  • Synthetic method of isavuconazole intermediate
  • Synthetic method of isavuconazole intermediate
  • Synthetic method of isavuconazole intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Preparation of compound 3

[0038] Under the protection of nitrogen, add 119g of magnesium powder and 6L of anhydrous tetrahydrofuran into a 10L four-neck round bottom flask, slowly add 1kg of 2,5-difluorobromobenzene, control the temperature not higher than 35°C, and drop difluorobromobenzene Continue the reaction until the magnesium powder disappears, slowly add 800g of compound (2) in anhydrous tetrahydrofuran solution (1L) dropwise, after reacting for 4h, slowly pour the reaction solution into 5L of saturated ammonium chloride aqueous solution, stir for 30min, let stand for liquid separation, water The phase was extracted with 5 L of ethyl acetate, and the organic phases were combined and concentrated to obtain 1.4 kg of crude intermediate (3). Recrystallization from ethyl acetate / n-heptane (1 / 4) gave 786 g of the refined product of intermediate (3), with a yield of 86%. Purity by HPLC: 98.2%.

[0039] 1 HNMR (500MHz, DMSO-d 6 )δ8.38(1H,s),7.85(1H,s),7.88–7.76(1...

Embodiment 2

[0055] Preparation of compound 3

[0056] According to the method of Example 1, the solvent was replaced by anhydrous THF; the reaction temperature was 20°C; the molar ratio of compound (2) and Grignard reagent was 1:1.0, and finally the refined product of intermediate (3) was obtained with a yield of 87% . Purity by HPLC: 98.8%.

[0057] Preparation of Compound 4

[0058] According to the method of Example 1, the reaction solvent is replaced by anhydrous toluene; the reaction temperature is 50 ° C; the mol ratio of compound (3) and acetaldehyde is 1:1; the alkali used in the reaction is replaced by sodium carbonate, catalyst and compound ( The molar ratio of 3) is 1:20, and finally the refined product of compound (4) is obtained with a yield of 78%. Purity by HPLC: 98.8%.

[0059] Preparation of compound 1

[0060] According to the method of Example 1, the solvent was replaced by water / DMSO, the volume ratio of which was 1:1, the reaction temperature was 22° C., and the ...

Embodiment 3

[0065] Preparation of compound 3

[0066] According to the method of Example 1, the solvent was replaced with anhydrous; the reaction temperature was 30°C; the molar ratio of compound (2) and Grignard reagent was 1:2, and finally the refined product of intermediate (3) was obtained with a yield of 88%. Purity by HPLC: 98.7%.

[0067] Preparation of Compound 4

[0068] According to embodiment 1 method, reaction solvent is replaced by anhydrous dichloromethane; Reaction temperature is 60 ℃; The mol ratio of compound (3) and acetaldehyde is 1:2.0; The base used in the reaction is replaced by triethylamine, catalyst and The molar ratio of compound (3) was 1:200, and finally the refined product of compound (4) was obtained with a yield of 81%. Purity by HPLC: 99.1%.

[0069] Preparation of compound 1

[0070] According to the method of Example 1, the solvent was replaced by water / butyl acetate, the volume ratio was 1:1, the reaction temperature was 35° C., and the reaction pH w...

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Abstract

The invention provides a synthetic method of a compound of a formula (1), i.e., an isavuconazole intermediate. By taking a compound of a formula (2) as a starting material, through a series of following reactions, the compound of the formula (1), i.e., the isavuconazole intermediate is finally obtained. Compared with a synthetic method more in isavuconazole intermediate synthesis step and complex in synthesis process in the prior art, the synthetic method is simple and practicable, low in cost, high in yield, good in product quality, and suitable for large-scale industrial production.

Description

technical field [0001] The invention relates to a method for synthesizing an isavuconazole intermediate, belonging to the technical field of synthesis of pharmaceutical intermediates. Background technique [0002] Isavuconazonium sulfate (common name: isavuconazoniumsulfate, trade name Cresemba), chemical name 1-[N-methyl-N-3-[(methylamino)acetylmethyl]pyridin-2-yl]methyl Acyloxy]ethyl-1-[(2R,3R)-2-(2,5-difluorophenyl)-2-hydroxy-3-[4-(4-cyano-phenyl)thiazole-2 -yl]butyl]-1H-[1,2,4]triazol-4-ium sulfate. The molecular weight of isavuconazole: 815; CAS registration number: 946075-13-4; the structural formula is shown in formula 1: [0003] [0004] Isavuconazole was developed by Astellas. An antifungal drug approved by the FDA on March 6, 2015, isavuconazole was approved in the United States for the treatment of aspergillosis and invasive mucormycosis. [0005] prior art literature [0006] Non-patent literature: Bioorg.Med.Chem.Lett., 2003, No.13, pp191-196; [0007]...

Claims

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Application Information

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IPC IPC(8): C12P17/10
CPCC12P17/10
Inventor 黄燕鸽
Owner 黄燕鸽