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Nickel catalyzed tedizolid phosphate synthesis method

A technology catalyzed by phosphate and nickel, which is applied in the fields of chemical instruments and methods, compounds of group 5/15 elements of the periodic table, organic chemistry, etc., can solve the problems of increasing operation steps and overall cost, and achieve improved synthesis efficiency, Avoid cumbersome steps, cheap effect

Active Publication Date: 2018-03-23
陕西思尔生物科技有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the synthesis and isolation of aryl boronic acids or boronic acid esters, and the use of more expensive palladium catalysts undoubtedly increase the number of steps and overall costs

Method used

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  • Nickel catalyzed tedizolid phosphate synthesis method
  • Nickel catalyzed tedizolid phosphate synthesis method
  • Nickel catalyzed tedizolid phosphate synthesis method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] 1. Dissolve 5.8g (20mmol) of the compound of formula I and 2.0g (30mmol) of imidazole in 50mL of DMF, add 3.6g (24mmol) of tert-butyldimethylsilyl chloride after dissolution, and react at 60°C for 6 hours; 200mL of water was added to the solution to dilute, and a large amount of white solid was precipitated. After filtration, the filter cake was washed with water (20mL×5), dried and then recrystallized (ethyl acetate / n-hexane) to obtain white filamentous crystals, namely the compound of formula II-1 (7.9 g, 98% yield).

[0033]

[0034] 2. In the absence of water and oxygen, put 20.2g (50mmol) of the compound of formula II-1 into a 250mL eggplant-shaped reaction flask, add 60mL of dry tetrahydrofuran to dissolve, and cool to -78°C. Then slowly add 20mL of 2.5mol / L n-butyllithium n-hexane solution dropwise, after the dropwise addition, continue the reaction at -78°C for 1 hour, then slowly add 60mL of 1.0mol / L anhydrous zinc chloride solution in tetrahydrofuran, Afte...

Embodiment 2

[0043] In step 2 of Example 1, the anhydrous zinc chloride used was replaced with anhydrous zinc bromide in an equimolar amount, and the yield of the compound of formula V-1 was 86%, and other steps were the same as in Example 1.

Embodiment 3

[0045] In step 2 of Example 1, under anhydrous and oxygen-free conditions, 20.2 g (50 mmol) of the compound of formula II-1 was placed in a 250 mL eggplant-shaped reaction flask, dissolved by adding 60 mL of dry tetrahydrofuran, and cooled to -78°C. Then slowly add 20mL 2.5mol / L n-butyllithium n-hexane solution dropwise, after the dropwise addition, continue the reaction at -78°C for 1 hour, then slowly add 60mL 1.0mol / L anhydrous zinc chloride solution in tetrahydrofuran, After the dropwise addition, the stirring reaction was continued for 30 minutes to generate the intermediate shown in formula III-1. Directly, the reaction solution was slowly raised to room temperature, and then 6.1g (25mmol) compound of formula IV, 1.61g (3.0mmol) bis[(2-diphenylphosphino)phenyl]ether (DPEPhos) and 545mg (2.5mmol) were added successively. ) Nickel bromide and 5 mL of 1.0 mol / L isopropylmagnesium chloride in tetrahydrofuran. The reaction was stirred at room temperature, and the progress of...

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Abstract

The invention discloses a nickel catalyzed tedizolid phosphate synthesis method. The method includes that methyl tetrazolium bromopyridine serving as an electrophilic reagent and N-oxazolidinone phenyl zinc halide serving as a nucleophilic reagent are subjected to nickel catalyzed Negishi coupling reaction and in-situ deprotection to obtain pharmaceutically active molecular tedizolid through a two-step one-pot process, and tedizolid is subjected to phosphoric acid esterification to obtain tedizolid phosphate. The method has advantages that 1) by in-situ synthesis and utilization of the organiczinc reagent, a complex step of metal reagent separation is avoided; 2) a cheap nickel catalyzing system is applied to establishment of a tedizolid phosphate core framework for the first time, and efficiency of nickel catalyzed Negishi coupling reaction is equivalent to that of palladium catalyzed Suzuki coupling reaction in current industrial synthesis of tedizolid phosphate. The remarkable advantages are beneficial to improvement of efficiency in tedizolid phosphate synthesis and production cost reduction, and the nickel catalyzed tedizolid phosphate synthesis method has a promising industrial application prospect.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis, and in particular relates to a synthesis method of antibacterial drug tedizolib phosphate. Background technique [0002] Tedizolid Phosphate, also known as Tedizolid Phosphate, English name Tedizolid Phosphate, trade name Sivextro (CAS No: 856867-55-5). Tedizolid Phosphate is a second-generation oxazolone antibiotic developed by Cubist, and was approved by the US FDA in June 2014. It is mainly used for the treatment of Staphylococcus aureus and various Streptococcus and other Gram Skin or tissue infections caused by positive bacteria. Tedizolid Phosphate has high activity and broad antibacterial spectrum, and its dosage is one-third of that of the first-generation linezolid, and it is expected to replace the nearly US$1.5 billion market that the latter has created. [0003] [0004] The key to the synthesis of tedizolid phosphate lies in the construction of its core skeleton, that...

Claims

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Application Information

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IPC IPC(8): C07F9/6558
CPCY02P20/55C07F9/65583
Inventor 黄治炎王俊亚王作弟任娟张安薛东杨俊刘建斌
Owner 陕西思尔生物科技有限公司
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