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Preparation method for tedizolid

A technology of tedizolid and tedizolid phosphate, which is applied in the field of medicinal chemistry synthesis, can solve the problem of not finding tedizolid and the like, and achieves the effects of mild conditions, mild reaction conditions and strong reaction selectivity.

Inactive Publication Date: 2015-09-09
成都美域高制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] At present, there is no method for preparing tedizolid by converting fragment B formula I into boronic acid and its derivatives and coupling with fragment A through metal catalysis

Method used

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  • Preparation method for tedizolid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Example 1 Formula II: Preparation of 5-bromo-2-(2H-tetrazol-5-yl)pyridine

[0039] Add 5-bromo-2-cyanopyridine (50 g, 273.22 mmol, 1 weight), N, N-dimethylformamide (400 ml, 8 volumes), chlorine Ammonium chloride (21.52g, 409.83mmol, 1.5 equivalents), sodium azide (26.64g, 409.83mmol, 1.5 equivalents), the oil bath temperature was set at 75°C (target temperature 80°C), the temperature reached 80°C within 20 minutes, and the reaction Continue self-heating to 84°C. After 1 hour, HPLC analysis shows that the initial raw materials are completely consumed, and the ammonium tetrazolium salt content is 92.1%, which means that the reaction is complete. The mixture was cooled, vacuum filtered at room temperature, the filter cake was washed with isopropanol (50ml, 1 vol), and dried under vacuum at 55°C to obtain 52.3g of white solid, yield 81.97%, HPLC: 95.7%.

Embodiment 2

[0040] Example 2 Preparation of Formula II 5-bromo-2-(2-methyl-2H-tetrazol-5-yl)pyridine

[0041]In a 1L three-neck flask equipped with mechanical stirring, add tetrazolium ammonium salt (52.3g, 222.56mmol, 1 weight), tetrahydrofuran (313ml, 6 volumes), N,N-dimethylformamide (105ml , 2 volumes) and sodium hydroxide powder (22.56 g, 556.4 mmol, 2.5 equiv). The maximum internal temperature of the reaction device was allowed to be 10°C, and then methyl iodide (78.9g, 556.4, 2.5 equivalents) was added dropwise, keeping the temperature below 10°C, and the addition of methyl iodide was completed within 40 minutes. After the dropwise addition was completed, remove the ice bath, install a thermocouple heater and a reflux cooler on the reaction device, set the external temperature to 30°C, and continue the reaction to self-heat to 44°C. After 4 hours, the reaction was detected by HPLC, ammonium tetrazolium The salt was completely consumed and the reaction was judged complete. The mix...

Embodiment 3

[0045] Example 3: (5R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl Synthesis of Formula Ⅰ of ]-5-(Hydroxymethyl)-2-oxazolidinone

[0046] Add (5R)-3-(4-iodo-3-fluorophenyl)-5-hydroxymethyloxazolidin-2-one (10g, 29.67 mmol, 1 weight), double pinacol borate (32.90 mmol), potassium acetate (8.74 g, 89.01 mmol), dioxane (100 ml, 10 volumes).

[0047] Nitrogen gas bubbled for 20 minutes to replace the oxygen and water in the there-necked flask, and then added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (1.09g, 1.48mmol, 5%), continue nitrogen bubbling for 5 minutes, set the temperature to 80°C, raise the temperature to 80°C within 30 minutes, HPLC analysis after 3 hours, the initial raw materials have completely reacted, tedizolid intermediate I; (5R)-3 -[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-5-(hydroxymethyl) - The content of 2-oxazolidinone is 93.4%. It is judged that the reaction is complete. ...

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Abstract

The invention discloses a preparation method for tedizolid as shown in a formula IV. According to the method, tedizolid is prepared through chemical combination of a compound as shown in a formula I and a compound as shown in a formula II via a coupling reaction; and tedizolid phosphate with medical purposes can be prepared by subjecting the obtained tedizolid to esterification by phosphate. The preparation method has the advantages of milder reaction conditions, a few produced impurities and simple post-treatment. According to the invention, the reaction mechanism of Suzuki-Miyaura coupling is employed to connect boric acid as shown in the formula I and derivatives thereof with the compound as shown in the formula II, so reaction selectivity is high, a few impurities are produced, and a synthetic ratio is more than 90%; and oxazolidinone borate is used to react with tetrazole, so conditions are milder, and the generation rate of impurities is lower.

Description

technical field [0001] The invention relates to the field of pharmaceutical chemical synthesis, in particular to a method for preparing tedizolid by using oxazolidinone compounds. Background technique [0002] Antibiotics are one of the most frequently used basic medicines in clinical practice. The non-standard use of antibiotics due to historical reasons has caused serious bacterial resistance to existing antibiotics. Multidrug-resistant (MDR) bacterial infections have become one of the major threats to global public health. Because of multidrug resistance, the combination of antibiotics is also increasing, and drug-drug interactions also increase the risk of adverse reactions. According to the 2013 National Adverse Drug Reaction Monitoring Annual Report released by the State Food and Drug Administration recently, the adverse reactions caused by antibiotics rank first in the adverse reaction / event reports. "Superbugs" resistant to the vast majority of currently available...

Claims

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Application Information

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IPC IPC(8): C07D413/14C07F9/6558A61P31/04A61P17/00
CPCC07D413/14C07F9/65583
Inventor 王春燕梁家智晏宾
Owner 成都美域高制药有限公司
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