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Racemic recovery method of by-product in resolution mother liquor of intermediate of sitafloxacin

A technology of sitafloxacin and recovery method, applied in the direction of organic racemization, organic chemical method, chemical instrument and method, etc., to achieve the effect of reducing production cost, obvious economic and social benefits, and good application prospects

Active Publication Date: 2018-11-30
WUHAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The by-product formula (1R,2R)-2-fluorocyclopropane carboxylic acid and (1S,2R)-2-fluorocyclopropane carboxylic acid obtained after the resolution of the intermediate reported in the above literature has no relevant literature at present and patent reports for racemization recovery; therefore, the development of a method for splitting by-products in mother liquor with good industrial application prospects has received great attention from relevant scientific researchers

Method used

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  • Racemic recovery method of by-product in resolution mother liquor of intermediate of sitafloxacin
  • Racemic recovery method of by-product in resolution mother liquor of intermediate of sitafloxacin
  • Racemic recovery method of by-product in resolution mother liquor of intermediate of sitafloxacin

Examples

Experimental program
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Effect test

Embodiment 1

[0035] [Example 1] Preparation of 2-fluorocyclopropane-1-carbaldehyde (VII)

[0036]Under anhydrous and oxygen-free conditions, 7.62 g of oxalyl chloride was slowly added to a mixture of 50 mL of DCM and 3.07 g of DMF, stirred at 0°C for 1 h, and spin-dried at room temperature for use. Under anhydrous and oxygen-free conditions, add 45mL acetonitrile, 80mL THF, and cool to -30°C. Mix 4.16g trans-2-fluoro-cyclopropanecarboxylic acid, 3.21g pyridine, and 80mL THF evenly, add the mixture into the reaction flask within 30min, stir at -30°C for 1h, and stir at -20°C for 30min. Cool to -90°C, add 34mL of 0.046mol tri-tert-butoxylithium aluminum hydride into the reaction flask within 30 minutes, and stir at -90°C for 30 minutes. After the reaction, add 50mL of 2M dilute hydrochloric acid to the reaction flask, remove from the ice bath, extract three times with 50mL of ether, add 50mL of saturated sodium bicarbonate solution (twice) and 50mL of H 2 After washing with O, anhydrous so...

Embodiment 2

[0037] [Example 2] Preparation and racemization treatment of 3-(2-fluorocyclopropyl) allyl)benzene (VIII)

[0038] Under anhydrous and oxygen-free conditions, add 2-bromoethylbenzene into the reaction flask of phosphorus oxychloride, use toluene as solvent, reflux for 12 hours, and spin dry to obtain phosphorus ylide solid with a yield of 72%. 1 H NMR (400MHz, CDCl 3 ( m,2H). Then, under anhydrous and oxygen-free conditions, 0.367g of the phosphorus ylide intermediate obtained above, 2mL THF and 0.56 potassium tert-butoxide were added, refluxed for 1h, cooled to room temperature, 0.1g trans-2-fluorocyclopropanecarbaldehyde, refluxed for 2h. After the reaction was completed, it was washed with saturated sodium bicarbonate and extracted with ethyl acetate. After drying the organic phase the product is purified by chromatography.

[0039] Racemization preparation process: In a three-necked flask equipped with a dropping device, add 1.5g of 3-(2-fluorocyclopropyl)allyl)benzene...

Embodiment 3

[0040] [Example 3] Preparation of 2-fluorocyclopropane-1-carboxylic acid (II)

[0041] 1.0 g of potassium permanganate was added in batches to the ethanol solution of 3-(2-fluorocyclopropyl)allyl)benzene (VIII), the mixture was heated to 70° C. for 3 h, then heated to 90° C. for 4 h. After the reaction was completed, the reactant was filtered and washed with hot water. Rotary evaporation under reduced pressure until about 10 mL of the reaction solution remained, slowly added 1M HCl until pH = 4, and dried. After purification by column chromatography, a white solid product was obtained with a yield of 49%. The relative contents of the four isomers are: (1S, 2S) 4.5, (1R, 2R) 4.5, (1R, 2S) 45.46, (1S, 2SR) 45.54. 1 H NMR (400MHz, DMSO-d 6 )δ 11.06(s,1H), 5.05–4.67(m,1H), 2.13–1.90(m,1H), 1.56–1.31(m,1H), 1.26–1.08(m,1H).

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Abstract

The invention discloses a racemic recovery method of the by-product in a resolution mother liquor of an intermediate of sitafloxacin. The method specifically comprises following steps: (1) carrying out resolution on a raceme 2-fluorocyclopropanecarboxylic acid to obtain by-products (1R,2R)-2-fluorocyclopropanecarboxylic acid and (1S,2R)-2-fluorocyclopropanecarboxylic acid; (2) carrying out a reduction reaction on the recovered by-products to obtain trans-2-fluorocyclopropane formaldehyde; (3) converting the trans-2-fluorocyclopropane formaldehyde into trans(3-(2-fluorocyclopropyl)allyl)benzene; and (4) carrying out racemization on the trans(3-(2-fluorocyclopropyl)allyl)benzene, and carrying out further oxidation and resolution to obtain the sitafloxacin intermediate which is (1S,2S)-2-fluorocyclopropanecarboxylic acid. Therefore, the invention provides the racemic recovery method of the trans-intermediate of the by-product of the sitafloxacin, and the racemic recovery method is mild incondition and simple and convenient in operation, and is capable of industrialized application and production.

Description

technical field [0001] The invention relates to the field of preparation of pharmaceutical intermediates, in particular to the racemization of by-products in the resolution mother liquor of an intermediate (1S,2S)-2-fluorocyclopropanecarboxylic acid having a broad-spectrum antibacterial drug-sitafloxacin recovery method. Background technique [0002] Sitafloxacin is a new type of quinolone antibiotics, clinical application shows that it has good antibacterial activity against both Gram-positive and Gram-negative bacteria. The structure-activity relationship research shows that the introduction of the cis-fluoropropylamine group in the structure improves the selectivity of sitafloxacin for bacterial enzymes, and is beneficial to reduce the toxic and side effects of quinolones. (1S,2S)-2-Fluorocyclopropanecarboxylic acid is a key intermediate in the synthesis of sitafloxacin. The published literature reports are as follows. [0003] First, the following classic synthesis me...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C61/15C07C47/353C07C23/18C07C45/41C07C51/16C07C51/487C07C17/263C07B57/00
CPCC07B57/00C07B2200/07C07C17/2635C07C45/41C07C51/16C07C51/487C07C2601/02C07C61/15C07C47/353C07C23/18
Inventor 周海兵杨录蒙秋妤
Owner WUHAN UNIV
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