A kind of preparation method of tedizolid impurity

A technology of tedizolid and impurities, which is applied in the field of preparation of tedizolid impurities, and achieves the effect of reasonable synthesis route, few steps and simple operation method

Active Publication Date: 2022-06-28
BEIJING WINSUNNY PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] Have not seen the synthetic method of tedizolid impurity (following structural formula) reported in public information yet at present, and tedizolid must have qualified impurity as standard reference substance when carrying out quality analysis, therefore provide a kind of simple to operate, easy to purify, The synthesis method of this impurity that can obtain high yield is of great significance to the quality research of tedizolid, and provides important guiding significance for the clinical drug safety of tedizolid

Method used

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  • A kind of preparation method of tedizolid impurity
  • A kind of preparation method of tedizolid impurity
  • A kind of preparation method of tedizolid impurity

Examples

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Comparison scheme
Effect test

Embodiment 1

[0029] Example 1: Preparation and purification of tedizolid impurities 1

[0030] Synthesis steps: add 100 mL of THF and 5.50 g (13.6 mmol) of compound A (R 1 =-CH 3 , R 2 =-CH 2 Ph), stir and mix well, add 12.8 mL of a THF solution of 1.6 mol / L lithium diisopropylamide at a temperature of 25 to 35 °C, keep at 20 to 30 °C and stir for 1 hour. Add 1.74g (13.6mmol) DMPU under temperature control at 20~30°C, cool down to 0~10°C, then add 1.96g (13.6mmol) (R)-glycidyl butyrate, first stir at 0~10°C for 30 minutes, then The temperature was raised to 20-30° C. and the reaction was stirred, and the reaction was monitored by TLC until the end of the reaction. Through HPLC analysis, 3.01 g of tedizolid impurity was obtained, and the yield was 62%.

[0031] Preparation steps of crude tedizolid impurity: after the reaction is completed, add 0.6 mL of saturated methanol solution of sodium methoxide, stir at 20-30 °C for 1 hour, then cool down to 0-10 °C, add 15 mL of saturated aqueous...

Embodiment 2

[0034] Example 2: Preparation and purification of tedizolid impurities 2

[0035] Synthesis steps: add 100 mL of 2-methyltetrahydrofuran and 5.45 g (13.6 mmol) of compound A (R 1 =-OCH 2 CH 2 CH 3 , R 2 =-CH 2 CH 2 CH 3 ), stir and mix well, add 17 mL of a 2-methyltetrahydrofuran solution of 1.6 mol / L n-butyllithium at a temperature of 25 to 35 °C, keep at 20 to 30 °C and stir for 1 hour. The temperature was controlled at 20~30°C, 17.4g (136mmol) DMPU was added, the temperature was lowered to 0~10°C, then 1.39g (13.6mmol) (R)-glycidyl formate was added, and the temperature was stirred at 0~10°C for 30 minutes, and then the temperature was increased. The reaction was stirred at 20-30° C., and the reaction was monitored by TLC until the end of the reaction. Through HPLC analysis, the impurity yield of tedizolid was 60%.

[0036] Preparation steps of crude tedizolid impurity: after the reaction is completed, add 0.6 mL of saturated methanol solution of sodium methoxide, s...

Embodiment 3

[0038] Example 3: Preparation and purification of tedizolid impurities 3

[0039] Synthesis steps: add 100 mL of ether, 6.29 g (13.6 mmol) of compound A (R 1 =-CH 2 Ph, ), stir and mix well, add 15 mL of a THF solution of 1.6 mol / L lithium bis(trimethylsilyl)amide at a temperature of 25 to 35 °C, keep at 20 to 30 °C and stir for 1 hour. Add 8.7g (68mmol) DMPU under temperature control at 20~30°C, cool down to 0~10°C, then add 1.96g (13.6mmol) (R)-glycidyl butyrate, stir at 0~10°C for 30 minutes, then heat up The reaction was stirred at 20-30° C., and the reaction was monitored by TLC until the end of the reaction. Through HPLC analysis, the impurity yield of tedizolid was 60%.

[0040] Preparation steps of crude tedizolid impurity: after the reaction is completed, add 0.6 mL of saturated methanol solution of sodium methoxide, stir at 20-30 °C for 1 hour, then cool down to 0-10 °C, add 15 mL of saturated aqueous ammonium chloride solution to quench the reaction, and control...

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Abstract

The invention relates to a preparation method of tedizolid impurity, which comprises the steps of treating compound A with a strong base in the presence of oxygen, adding glycidyl ester, and reacting to obtain tedizolid impurity. The high-purity tedizolid impurity can be prepared by the method, and the method has high yield and simple operation, and the product can be used as a reference substance of the tedizolid impurity, and then the purity of the intermediate is monitored in the synthesis process of the tedizolid.

Description

technical field [0001] The invention relates to the fields of organic synthesis such as medicines, pesticides and dyes, in particular to a preparation method of tedizolid impurities. Background technique [0002] Tedizolid is an oxazolidinone antibiotic developed by East Asia Pharmaceutical Company of South Korea. Tedizolid was approved by the U.S. FDA in June 2014. The drug is the first FDA-approved second-generation oxazolidinone antibiotic. Compared with the first-generation product linezolid, the drug's in vitro inhibitory activity against some bacteria is 2-8 times higher, and it is safe to a certain extent. also improved. [0003] CN200980140144 discloses a kind of preparation method of tedizolid, wherein the step of preparing tedizolid, the reaction formula is as follows, but in this reaction, the tedizolid impurity that demethylates will be generated, and this impurity is due to the difference between tedizolid and tedizolid. Similar in structure, chemical and phy...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D413/14
CPCC07D413/14
Inventor 刘岩松林国良王书成李雅梨
Owner BEIJING WINSUNNY PHARMA CO LTD
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