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Synthesis process of S-(-)-nadifloxacin chiral intermediate

A chiral intermediate, nafloxacin technology, applied in the directions of silicon organic compounds, organic chemistry, organic chemistry methods, etc., can solve the problems of low compound utilization rate and high cost of chemical resolution methods, and improve chiral selectivity. , the effect of increasing solubility and improving yield

Active Publication Date: 2021-10-22
湖南中威制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] The technical problem to be solved in the present invention: the chemical resolution method cost is higher in the existing S-(-)-nafloxacin chiral intermediate obtaining method, the technical problem that the utilization rate of compound is low

Method used

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  • Synthesis process of S-(-)-nadifloxacin chiral intermediate
  • Synthesis process of S-(-)-nadifloxacin chiral intermediate
  • Synthesis process of S-(-)-nadifloxacin chiral intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Chiral ligands are made by the following steps:

[0034] S1. Add 30 mL of ethanol into a three-necked flask equipped with a magnetic stirrer, a thermometer and a reflux condenser, heat the temperature of the reaction system to 35°C, then add 1.6 mol of deionized water and 10 mL of hydrochloric acid, stir for 25 minutes, and dropwise add 0.75 mol of the mixture of triethoxysilane and epoxybutyltrimethoxysilane, the dropping rate is 1 drop / second, after the addition is complete, the hydrolysis reaction is continued for 3 days, and then the pH of the reaction solution is adjusted to neutral with NaOH aqueous solution. The solvent was removed by distillation under reduced pressure, washed twice with deionized water, dried over anhydrous magnesium sulfate, and filtered to obtain epoxy polysilsesquioxane; containing phenyl triethoxy silane and epoxy butyl trimethoxy The molar ratio of phenyltriethoxysilane to epoxybutyltrimethoxysilane in the mixture of base silane is 6.8:1, ...

Embodiment 2

[0039] Chiral ligands are made by the following steps:

[0040] S1. Add 50 mL of ethanol into a three-necked flask equipped with a magnetic stirrer, a thermometer and a reflux condenser, heat the temperature of the reaction system to 35°C, then add 1.6 mol of deionized water and 12 mL of hydrochloric acid, stir for 25 minutes, and dropwise add 0.8 mol of the mixture of oxybutyltriethoxysilane and epoxybutyltrimethoxysilane, the rate of addition is 1 drop / second, after the addition is complete, the hydrolysis reaction is continued for 3 days, and then the pH of the reaction solution is adjusted to neutral with NaOH aqueous solution. The solvent was removed by distillation under reduced pressure, washed 2-4 times with deionized water, dried over anhydrous magnesium sulfate, and filtered to obtain epoxy polysilsesquioxane; containing phenyltriethoxysilane and epoxybutyl The molar ratio of phenyltriethoxysilane and epoxybutyltrimethoxysilane in the mixture of trimethoxysilane is 7...

Embodiment 3

[0048] Chiral catalysts are made by the following steps:

[0049] Add 0.1 mmol RuCl to the three-necked flask under nitrogen protection 3 ·xH 2 O and 0.21 mmol of the chiral ligand prepared in Example 1, then added 6 mL of DMF that had been treated with dehydration and oxygen removal, stirred at 100°C for 1 h, cooled to room temperature, stirred overnight, vacuum-dried the DMF at 35°C, and removed the residue Dichloromethane was added to the mixture, filtered under nitrogen protection, the filtrate was concentrated in vacuo, n-hexane was added, and filtered under nitrogen protection to obtain a chiral catalyst.

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Abstract

The invention discloses a synthesis process of an S-(-)-nadifloxacin chiral intermediate, and belongs to the technical field of chemical pharmacy. The synthesis process comprises the following steps: 1, synthesizing an intermediate 1; and 2, synthesizing the S-(-)-chiral intermediate. R binaphthylenediamine is used as a matrix of a chiral ligand, epoxy polysilsesquioxane is grafted on a molecule of N-Boc-L-histidine to form the chiral ligand, on one hand, the ee value is increased by utilizing the chiral characteristic of N-Boc-L-histidine, and on the other hand, the ee value is increased by utilizing the characteristics of nanoscale size and solubility of the epoxy polysilsesquioxane, so that the solubility of the catalyst is increased, and the catalyst can be mixed with the reactant in the nanometer size so as to improve the catalytic performance of the chiral catalyst and improve the reaction yield, such that the chiral ligand and the metal ruthenium are subjected to coordination to form the chiral catalyst so as to provide the good chiral amplification effect;.

Description

technical field [0001] The invention belongs to the technical field of chemical pharmacy, and in particular relates to a synthesis process of an S-(-)-nafloxacin chiral intermediate. Background technique [0002] Nafloxacin was developed by Otsuka Corporation of Japan and belongs to the third generation of quinolone antibacterial drugs. It is used externally to treat acne and folliculitis. It was first launched in Japan in 1993 (trade name: Acuatim), in 2004 in Germany (trade name: Nadixa), and in 2005 in China (trade name: Eunion, 1% ointment). [0003] Because of its absorption and vascular irritation, nafloxacin can only be made into external preparations for acne caused by propionibacterium acnes in vitro. Among them, S-(-)-nafloxacin is the main active isomer, and its antibacterial activity is 64-256 times that of the R-type isomer and twice that of the racemate. [0004] The synthesis process of nafloxacin is generally based on 3,4-difluoro-6-bromoacetanilide as the ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F7/21
CPCC07F7/21C07B2200/07
Inventor 常国树姜明姣周航徐果果雷腊
Owner 湖南中威制药有限公司
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