One-pot synthesized tedizolid

A technology of tedizolid and tetrazole, applied in the field of preparation of tedizolid, can solve problems such as unfavorable scale-up production, harsh reaction conditions, complicated operation process, etc., and achieves reduction of material transfer, processing cost, and solvent reduction. effect of dosage

Inactive Publication Date: 2017-11-24
HANGZHOU XINBOSI BIOMEDICAL CO LTD
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AI Technical Summary

Problems solved by technology

[0012] The cost of the catalyst used in this method is high, the bis(trimethylsilyl)amide lithium used in the second step requires anhydrous conditions, the reaction conditions are relatively harsh, and the post-treatment is relatively cumbersome, which is not conducive to scal

Method used

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  • One-pot synthesized tedizolid
  • One-pot synthesized tedizolid

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Under stirring, 1,4-dioxane (300 ml), 5-bromo-2-(2-methyl-2H-tetrazol-5-yl)pyridine (20.0 g, 83.3 mmol , 1.0 equiv), pinacol diboronate (21.2 g, 83.3 mmol, 1.0 equiv), potassium acetate (24.5 g, 250 mmol, 3.0 equiv), and tetrakis(triphenylphosphine)palladium (2.0 g, 1.7 mmol, 0.02 equivalent). The temperature was raised to reflux under the protection of nitrogen, and the reaction of 5-bromo-2-(2-methyl-2H-tetrazol-5-yl)pyridine was followed by TLC to complete the reaction.

[0033] After the reaction is completed, cool to below 10°C, and add (5R)-3-(4-bromo-3-fluorophenyl)-5-hydroxymethyloxazolidin-2-one (24.1 g, 83.3 mmol, 1.0 equivalent), potassium carbonate (34.5 g, 250 mmol, 3.0 equivalent) and tetrakis(triphenylphosphine)palladium (0.96 g, 0.83 mmol, 0.01 equivalent), nitrogen protection. Warming up to reflux, TLC tracking 2-(2-methyl-2H-tetrazol-5-yl)-5-(4,4,5,5-tetramethyl-1,3-dioxaborolane-2- Base) pyridine reacts completely.

[0034] After the reaction was ...

Embodiment 2

[0036] Under stirring, 1,4-dioxane (400 ml), 5-bromo-2-(2-methyl-2H-tetrazol-5-yl)pyridine (20.0 g, 83.3 mmol , 1.0 equiv), pinacol diboronate (25.3 g, 100 mmol, 1.2 equiv), potassium acetate (20.4 g, 208 mmol, 2.5 equiv), and bis(triphenylphosphine)palladium dichloride (1.17 g, 1.4 mmol, 0.015 equiv). The temperature was raised to reflux under the protection of nitrogen, and the reaction of 5-bromo-2-(2-methyl-2H-tetrazol-5-yl)pyridine was followed by TLC to complete the reaction.

[0037] After completion of the reaction, cool to below 20°C, add (5R)-3-(4-bromo-3-fluorophenyl)-5-hydroxymethyloxazolidin-2-one (21.7 g, 75.0 mmol, 0.9 equiv), potassium carbonate (34.5 g, 250 mmol, 3.0 equiv), palladium acetate (0.14 g, 0.62 mmol, 0.0075 equiv) and triphenylphosphine (0.65 g, 2.5 mmol, 0.03 equiv), under nitrogen protection. Warming up to reflux, TLC tracking 2-(2-methyl-2H-tetrazol-5-yl)-5-(4,4,5,5-tetramethyl-1,3-dioxaborolane-2- Base) pyridine reacts completely.

[0038]A...

Embodiment 3

[0040] Under stirring, 1,4-dioxane (400 ml), 5-bromo-2-(2-methyl-2H-tetrazol-5-yl)pyridine (20.0 g, 83.3 mmol , 1.0 equiv), pinacol diboronate (23.3 g, 91.6 mmol, 1.1 equiv), potassium phosphate (35.3 g, 167 mmol, 2.0 equiv) and [1,1'-bis(diphenylphosphino) di Ferrocene]palladium dichloride (0.61 g, 0.83 mmol, 0.01 equiv). The temperature was raised to reflux under the protection of nitrogen, and the reaction of 5-bromo-2-(2-methyl-2H-tetrazol-5-yl)pyridine was followed by TLC to complete the reaction.

[0041] After the reaction is completed, cool to below 25 °C, add water (60 ml), (5R)-3-(4-bromo-3-fluorophenyl)-5-hydroxymethyloxazolidine-2- Ketone (26.5 g, 91.4 mmol, 1.1 equiv), cesium carbonate (54.3 g, 167 mmol, 2.0 equiv), palladium chloride (0.14 g, 0.62 mmol, 0.01 equiv) and triphenylphosphine (0.65 g, 2.5 mmol, 0.04 equivalent), nitrogen protection. Warming up to reflux, TLC tracking 2-(2-methyl-2H-tetrazol-5-yl)-5-(4,4,5,5-tetramethyl-1,3-dioxaborolane-2- Base) p...

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Abstract

The invention relates to a preparation method of tedizolid indicated in the formula I. The preparation method includes: taking 5-bromine-2-(2-methyl-2H-tetrazole-5-radical) pyridine indicated in the formula II as a raw material to be reacted with boric acid indicated in the formula III to obtain 2-(2-methyl-2H-tetrazole-5-radical)-5-(4,4,5,5-tetramethyl-1,3-dioxane-2-radical) pyridine indicated in the formula IV under the action of a palladium catalyst; allowing compound without separation to be directly in Suzuki coupling reaction with (5R)-3-(4-bromine-3-fluorophenyl)-5-hydroxymethyl oxazolane-2-ketone indicated in the formula V under the action of the palladium catalyst to obtain the tedizolid indicated in the formula I. The preparation method of the one-pot synthesized tedizolid is easy in obtaining of the raw materials, simple in production process, short in production cycle, less in discharge of three wastes (waste gas, waste water and industrial residue), and a one-pot method is high in yield and has great practical value.

Description

technical field [0001] The invention relates to the field of medicine and chemical industry, in particular to a preparation method of tedizolid. Background technique [0002] Tedizolid (compound I), is the active form of tedizolid phosphate, and is also an important intermediate in its synthesis process, the chemical name is (5R)-3-(3-fluoro-4-(6-( 2-Methyl-2H-tetrazol-5-yl)pyridin-3-yl)phenyl-5-hydroxymethyloxazolidin-2-one, the structural formula is as follows: [0003] [0004] Tedizolid Phosphate (Tedizolid Phosphate) is a new generation of oxazolidinone antibiotics developed by Cubist Pharmaceuticals for the treatment of Staphylococcus aureus (including methicillin-resistant strains, methicillin-sensitive strains) and various Acute bacterial skin and skin structure infection (ABSSSI) caused by Gram-positive bacteria such as Streptococcus and Enterococcus faecalis, the US FDA approved its marketing on June 20, 2014, under the trade name Sivextro. Sivextro is the fir...

Claims

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Application Information

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IPC IPC(8): C07D413/14
CPCC07D413/14
Inventor 王振宇诸惠刘艳华
Owner HANGZHOU XINBOSI BIOMEDICAL CO LTD
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