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Preparation method of isavuconazonium sulfate intermediate

A technology of isavuconazolium and intermediates, applied in the field of drug synthesis, can solve the problems of high risk of lithium tetrahydrogen, unfavorable industrial production, and inconvenient post-processing, so as to save energy consumption, be beneficial to environmental protection, and reduce side effects. less responsive effect

Inactive Publication Date: 2021-12-31
KAIFENG MINGREN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] In the above existing preparation methods, lithium aluminum hydride is used for catalytic hydrogenation, the reaction conditions are high, the reaction time is long, post-processing is inconvenient, and lithium aluminum hydride is highly dangerous, which is unfavorable for industrial production.

Method used

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  • Preparation method of isavuconazonium sulfate intermediate
  • Preparation method of isavuconazonium sulfate intermediate
  • Preparation method of isavuconazonium sulfate intermediate

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Embodiment 1

[0050] The preparation method of isavuconazolium sulfate intermediate of the present invention, the detailed steps of this preparation method are as follows:

[0051] a. Synthesis of 1-chloroethyl methylcarbamate:

[0052] Add 1500 mL of absolute ethanol and 204 g (3 mol) of sodium ethoxide into the reaction flask for stirring and dissolving. After fully dissolving, add 67.5 g (1 mol) of methylamine hydrochloride and stir for 30 min at room temperature. After the reaction, cool the resulting reaction solution to 0 ℃;

[0053] Then 143g (1mol) 1-chloroethyl chloroformate is dissolved in 1500mL dehydrated alcohol, and the gained 1-chloroethyl chloroformate ethanol solution after dissolving is slowly dripped in the above-mentioned cooling gained reaction solution, and the dropping time is 30min; After the dropwise addition, react at 0°C for 2h, filter after the reaction, and the obtained filtrate is methylcarbamate-1-chloroethyl ethanol solution;

[0054] b, (3-hydroxymethyl-py...

Embodiment 2

[0062] The preparation method of isavuconazolium sulfate intermediate of the present invention, the detailed steps of this preparation method are as follows:

[0063] a. Synthesis of 1-chloroethyl methylcarbamate:

[0064] Add 1360mL of absolute ethanol and 136.1g (2mol) of sodium ethoxide into the reaction flask and stir to dissolve. After fully dissolving, add 87.8g (1.3mol) of methylamine hydrochloride and stir at room temperature for 60min. After the reaction, cool the resulting reaction solution to -20°C;

[0065] Then 143g (1mol) 1-chloroethyl chloroformate is dissolved in 2145mL dehydrated alcohol, and the gained 1-chloroethyl chloroformate ethanol solution after dissolving is slowly dripped in the reaction solution obtained by the above-mentioned cooling, and the dropping time is 60min; After the dropwise addition, react at -10°C for 3h, filter after the reaction, and the obtained filtrate is methylcarbamate-1-chloroethyl ethanol solution;

[0066] b, (3-hydroxymethy...

Embodiment 3

[0074] The preparation method of isavuconazolium sulfate intermediate of the present invention, the detailed steps of this preparation method are as follows:

[0075] a. Synthesis of 1-chloroethyl methylcarbamate:

[0076] Add 1910mL of absolute ethanol and 272.2g (4mol) of sodium ethoxide into the reaction flask and stir to dissolve. After fully dissolving, add 81.0g (1.2mol) of methylamine hydrochloride and stir at room temperature for 45min. After the reaction, cool down the resulting reaction solution to -10°C;

[0077] Then 143g (1mol) 1-chloroethyl chloroformate is dissolved in 1700mL dehydrated alcohol, and the gained 1-chloroethyl chloroformate ethanol solution after dissolving is slowly dripped in the reaction solution obtained by the above-mentioned cooling, and the dropping time is 45min; After the dropwise addition, react at -5°C for 3h, filter after the reaction, and the obtained filtrate is methylcarbamate-1-chloroethyl ethanol solution;

[0078] b, (3-hydroxym...

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Abstract

The invention discloses a preparation method of an isavuconazonium sulfate intermediate. The preparation method comprises the following steps: firstly, reacting absolute ethyl alcohol, sodium ethoxide and methylamine hydrochloride, cooling an obtained reaction solution, adding an ethanol solution of 1-chloroethyl methylcarbamate for continuous reaction, and conducting filtering to obtain an ethanol solution of methyl carbamic acid-1-chloroethyl ester; cooling the obtained solution, adding an ethanol solution of 2-chloro-3-pyridinemethanol for stirring reaction, filtering a reactant, removing ethanol, adding dichloromethane for dissolving, conducting washing after dissolving, and taking an organic phase, namely a dichloromethane solution of 1-chloro-ethyl (3-hydroxymethyl-pyridin-2-yl)-methylcarbamate; and firstly adding BOC-sarcosine into the obtained solution, then adding carbodiimide and 4-dimethylaminopyridine in batches for a reaction, and performing treatment after the reaction, so as to obtain the isavuconazole onium sulfate intermediate. The isavuconazonium sulfate is prepared by using the technical scheme of the invention, the side reaction of the process is less, and the purity of the obtained product is high.

Description

1. Technical field: [0001] The invention relates to the technical field of drug synthesis, in particular to a preparation method of an isavuconazolium sulfate intermediate. 2. Background technology: [0002] Isavuconazole is an antifungal drug for the treatment of invasive aspergillosis and mucormycosis jointly developed by Baselia Pharmaceutical Co., Ltd. and Astellas Pharmaceuticals, and has been granted orphan status by the FDA and the European Medicines Agency drug qualifications. On March 6, 2015, the U.S. FDA gave priority to the listing of Astellas Isavuconazole Sulfate under the trade name Cresemba, and on October 15, 2015, the European Commission granted the marketing authorization of Basilea Pharmaceuticals Isavuconazole. [0003] The chemical name of isavuconazolium sulfate is N-methylglycine [2-[[[1-[1-[(2R,3R)-3-[4-(4-cyanophenyl)-2-thiazole Base]-2-(2,5-difluorophenyl)-2-hydroxybutyl]-4H-1,2,4-triazolium-4-yl]ethoxy]carbonyl]methylamino]-3 -pyridyl] methyl s...

Claims

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Application Information

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IPC IPC(8): C07D213/75
CPCC07D213/75
Inventor 李运铎张煜晨张永超李沁沁常欢张银霞王翠霞季萍张亚慧
Owner KAIFENG MINGREN PHARMA
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