Synthesis method of prulifloxacin key intermediate

A synthesis method and technology of pulifloxacin, which are applied in chemical instruments and methods, preparation of organic compounds, organic chemistry, etc., can solve the problems of increased cost, complicated reaction operation, etc., and achieve simple operation, simple process and mild reaction conditions. Effect

Pending Publication Date: 2021-07-30
ZHEJIANG UNIV OF TECH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0011] This route has a total of six steps, of which the second step uses toxic and harmful reagents such as diethyl sulfate, and the reaction operation is relatively complicated. At the same time, the fifth step reaction adopts column chromatography to separate and purify, which increases the cost of production

Method used

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  • Synthesis method of prulifloxacin key intermediate
  • Synthesis method of prulifloxacin key intermediate
  • Synthesis method of prulifloxacin key intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Example 1: Preparation of ethyl 3-(4-chloro-2,5-difluorophenyl)-3-oxopropionate (III)

[0036]

[0037] Add diethyl carbonate (47.2g, 0.4mol), sodium hydride (12g, 0.5mol) and 200mL toluene to a 500mL reaction flask, raise the temperature to a reaction temperature of 100-105°C, and slowly add 1-(4-chloro- 70 mL of toluene solution of 2,5-difluorophenyl)ethanone (II) (38 g, 0.2 mol) was added dropwise in about 2 hours, and the reaction was continued for 3 h after the dropwise addition was completed. After the reaction is completed, slowly cool to room temperature, adjust the pH to neutral with 5% dilute hydrochloric acid, separate layers, extract the water layer with toluene, combine the organic layers, concentrate under reduced pressure to recover three-quarters of the volume of toluene, and let stand Crystallization gave white solid compound (III) (46.1 g, yield 88%), melting point: 66-68°C.

[0038] 1 H NMR (400MHz, CDCl 3 )δ7.53(d, J=6.4Hz, 1H), 7.48(d, J=9.1Hz, ...

Embodiment 2 Embodiment 8

[0040] The preparation of 3-(4-chloro-2,5-difluorophenyl)-3-oxopropionic acid ethyl ester (III), the preparation method of each embodiment is repeated in Example 1, the difference is to change a certain reaction Conditions (such as the type of basic substance A, the ratio of the amount of compound (II) to basic substance A, reaction temperature, reaction time, etc.), the specific changes of the reaction conditions and corresponding reaction effects in each embodiment are shown in the table 1 in.

[0041] Table 1

[0042]

[0043] In conjunction with Table 1, the amount of sodium hydride charged in the preparation method of embodiment five is 0.3 mol, and the amount of sodium hydride charged in the preparation method of embodiment six is ​​0.6 mol. In the preparation methods of Examples 2-8, the feeding amount of 1-(4-chloro-2,5-difluorophenyl)ethanone is 0.2 mol.

Embodiment 9

[0044] Example 9: Preparation of ethyl 2-(4-chloro-2,5-difluorobenzoyl)-3,3-bis(ethylthio)acrylate (IV)

[0045]

[0046] Add ethyl 3-(4-chloro-2,5-difluorophenyl)-3-oxopropionate (III) (39g, 0.15mol), potassium carbonate (52g, 0.37mol), ethanol to a 500mL reaction flask 400mL, carbon disulfide (17g, 0.22mol), and iodoethane (58.5g, 0.37mol) was slowly added dropwise at 30-35°C, and the dropwise addition was completed in about 1 hour, and then the reaction was continued for 3h. Subsequent vacuum distillation reclaims ethanol, adjusts pH to neutrality with the dilute hydrochloric acid of mass concentration 5%, extracts with dichloromethane, separates layers, and the organic layer is concentrated to dryness under reduced pressure, obtains compound (IV) (56.1g, yield 95 %), the product is an orange-red liquid. The purity measured by HPLC was 97.2% (the mobile phase measured by HPLC was the volume ratio of acetonitrile and phosphoric acid aqueous solution=40:60, and the pH of ...

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Abstract

The invention discloses a synthesis method of a prulifloxacin key intermediate. The prulifloxacin key intermediate is 7-chloro-6-fluoro-1-methyl-4-oxo-1H,4H-[1,3]thiazolo[3,2-a]quinoline-3-carboxylic acid ethyl ester (I), the synthesis method comprises the following steps: taking 1-(4-chloro-2,5-difluorophenyl)ethanone (II) as an initial raw material, carrying out Claisen condensation to obtain a compound (III), carrying out ethylation on the compound (III) to obtain a compound (IV), carrying out ammonolysis on the compound (IV) and an ammoniation reagent, carrying out cyclization reaction under the action of potassium carbonate to obtain a compound (VI), carrying out hydroxyl protection on the compound (VI) by using acetyl chloride to obtain a compound (VII), carrying out chlorination reaction on the compound (VII) and a chlorination reagent, and then performing cyclization reaction under the action of sodium acetate to obtain an intermediate target product. The synthesis method disclosed by the invention has the characteristics of simple process, simplicity and convenience in operation, mild reaction conditions, avoidance of use of toxic and harmful reagents, reduction of environmental pollution, higher total yield and the like, thereby having higher implementation value and social and economic benefits.

Description

technical field [0001] The invention relates to the field of synthesis of pharmaceutical and chemical intermediates, in particular to the preparation of prifloxacin key intermediate 7-chloro-6-fluoro- A new method for ethyl 1-methyl-4-oxo-1H,4H-[1,3]thiazolo[3,2-a]quinoline-3-carboxylate. Background technique [0002] Prulifloxacin (PUFX for short) is a new generation of fluoroquinolone antibacterial drugs jointly developed by Nippon Shinyaku and Meiji Seika. It was approved for listing in Japan on July 31, 2002. The mechanism of action of the drug targets the DNA of the bacteria. By blocking the DNA topoisomerase, the bacterial DNA cannot form superhelixes, further causing irreversible damage to the chromosomes, resulting in the inability of the bacterial cells to divide and reproduce. Toxicological data show that when prifloxacin is administered orally, the rough median lethal dose of mice, rats and beagle dogs is not less than 5000mg / kg. No obvious reproductive toxicit...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D495/04C07D215/56C07C319/14C07C323/56C07C323/29C07C67/00C07C69/738
CPCC07D495/04C07D215/56C07C319/14C07C67/00C07C323/56C07C323/29C07C69/738
Inventor 陈志卫徐艺铖袁其亮陈寅镐王超
Owner ZHEJIANG UNIV OF TECH
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