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Preparation method of tedizolid phosphate

A technology of tedizolid phosphate and preparation steps, which is applied in the field of preparation of oxazolidinone antibiotic tedizolid phosphate, can solve the problems of difficulty in obtaining raw materials, increased side reactions, long preparation steps, etc., and achieves environmental protection of the process The effect of economy, promotion of development, and easy availability of raw materials

Inactive Publication Date: 2015-02-04
SUZHOU MIRACPHARMA TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] It can be seen from this that the existing preparation method has weaknesses such as long preparation steps, difficulty in obtaining raw materials, and high cost; the preparation and use of organotin reagents have relatively high requirements for equipment and the environment, and there are

Method used

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  • Preparation method of tedizolid phosphate
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  • Preparation method of tedizolid phosphate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028]

[0029] Under nitrogen atmosphere, add 2-(2-methyltetrazol-5-yl)pyridine-5-boronic acid (II) (2.15g, 10.5mmol), R-3-(3-fluoro- 4-iodo-phenyl)-2-oxo-5-oxazolidinylmethanol phosphate (III) (4.17g, 10mmol), tetrakis(triphenylphosphine)palladium (0.23g, 0.2mmol), 1M phosphoric acid Potassium solution 15mL and toluene 30mL were heated up to reflux, kept at reflux for 10-12 hours, and TLC detected that the reaction was complete. Add 30 mL of ethyl acetate, wash with water and saturated brine successively, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The resulting oil is recrystallized with n-hexane and ethyl acetate (1:1, V / V), and dried in vacuo to obtain a white Solid tedizolid phosphate (I) 3.82g, yield 84.9%, 1 H NMR (DMSO-d6): d 8.92(s, 1H), 8.20(m, 2H), 7.74(t, 1H), 7.66(dd, 1H), 7.50(dd, 1H), 4.95(m, 1H) , 4.46(s, 3H), 4.21(t, 1H), 4.05(m, 2H), 3.91(m, 1H), FAB-MS m / z: 451[M+H] + .

Embodiment 2

[0031]

[0032] Under a nitrogen atmosphere, 2-(2-methyltetrazol-5-yl)pyridine-5-boronic acid pinacid (II) (3.01g, 10.5mmol), R-3-(3 -Fluoro-4-bromo-phenyl)-2-oxo-5-oxazolidinylmethanol phosphate (III) (3.69g, 10mmol), [1,1'-bis(diphenylphosphino)dicene Iron] Palladium dichloride / dichloromethane complex (0.15g, 0.2mmol), potassium acetate (1.17g, 12mmol) and 50mL of 1,4-dioxane, heated to 110°C, stirred for 4-5 hours , TLC detected that the reaction was complete. Add 50 mL of ethyl acetate, wash with water and saturated brine successively, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The resulting oil is recrystallized with n-hexane and ethyl acetate (1:1, V / V), and dried in vacuo to obtain a white Solid tedizolid phosphate (I) 4.02g, yield 89.3%.

Embodiment 3

[0034]

[0035] Under a nitrogen atmosphere, 2-(2-methyltetrazol-5-yl)-5-bromo-pyridine (IV) (2.4g, 10mmol), bispinacol diborane ( 1.27g, 5mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (0.82g, 1mmol), potassium acetate (1.17g, 12mmol), and 1,4-dioxane 30mL , the temperature was raised to 110° C., and the reaction was stirred for 4 hours. Cool down to room temperature, still under nitrogen atmosphere, add R-3-(3-fluoro-4-bromo-phenyl)-2-oxo-5-oxazolidinylmethanol phosphate (III) (3.69 g, 10 mmol), 20 mL of 1,4-dioxane and 0.5 mL of 5M potassium phosphate, the temperature was raised to 100°C again, and the reaction was stirred for 4 hours, and the reaction was detected by TLC. Add 50 mL of ethyl acetate, filter, the filtrate is washed with water and saturated brine successively, dried over anhydrous sodium sulfate, concentrated under reduced pressure, the obtained oil is recrystallized with n-hexane and ethyl acetate (1:1, V / V), vacuum After drying, 3.34 g...

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Abstract

The invention discloses a preparation method of tedizolid phosphate (I). According to the preparation method, a compound as shown in the formula II and a compound as shown in the formula III have a coupling reaction to generate tedizolid phosphate (I). The preparation method adopts easily available raw materials and a simple process, is economical and environmentally friendly and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis route design and preparation of raw materials and intermediates, and in particular relates to a preparation method of a novel oxazolidinone antibiotic tedizolid phosphate. Background technique [0002] Tedizolid phosphate is an oxazolidinone antibiotic developed by Cubist Pharmaceuticals. Tedizolid phosphate was approved by the US FDA in June 2014 to be marketed in the US under the trade name Sivextro. The drug is the first second-generation oxazolidinone antibiotic approved by the FDA. Compared with the first-generation product linezolid, Sivextro has 2-8 times higher inhibitory activity against some bacteria in vitro, and its safety is also to a certain extent. improved. Since the compound Tedizolid does not yet have a standard Chinese translation, the applicant hereby transliterates it as "Tedizolid". [0003] The chemical name of Tedizolid phosphate is: {(5R)-3-[3-fluoro-4-[6-(2-m...

Claims

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Application Information

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IPC IPC(8): C07F9/6558
CPCC07F9/6558Y02P20/582
Inventor 许学农
Owner SUZHOU MIRACPHARMA TECH
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