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Preparation method for enrofloxacin-d5

A technology of deuterated enrofloxacin and -d5, which is applied in the fields of organic chemistry methods, chemical instruments and methods, isotope introduction of heterocyclic compounds, etc., and can solve the problems such as the inability to obtain isotopic abundances.

Active Publication Date: 2018-10-19
雅安职业技术学院
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, if the method disclosed in Patent 1 is directly designed as a coupling reaction without modifying the raw materials, good isotope abundance cannot be obtained

Method used

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  • Preparation method for enrofloxacin-d5
  • Preparation method for enrofloxacin-d5

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0052] Example 1: 4-Ethyl-1-Boc-piperazine- d 5 preparation of

[0053] 1-Boc-piperazine (2.42 g, 13 mmol) was mixed with CD 3 cd 2 I (1.47 g, 9 mmol) dissolved in CH 2 Cl 2 (20 mL), add K to the above mixture 2 CO 3 (1.8 g, 13 mmol), stirred at room temperature for 18 h, then added CD 3 cd 2 I (1.47 g, 9 mmol), continue stirring at room temperature for 18 h, after the reaction is complete, add H 2 O (10 mL), split CH 2 Cl 2 layer, water soluble with CH 2 Cl 2 Extract (2 × 10 mL), combine CH 2 Cl 2 layer, washed with saturated NaCl, anhydrous MgSO 4 Drying and concentration under reduced pressure gave 2.72 g yellow oil crude product 4-ethyl-1-Boc-piperazine- d 5 , the yield was 98%, and could be directly used in the next step without purification. ESI-MS(m / z): 220.1 (M+H) +1 , 1 HNMR (400 MHz, CDCl 3 ): δ = 3.43-3.45 (4H, m), 2.38-2.44(4H, m), 1.46 (9H, s).

example 2

[0054] Example 2: 1-Ethyl-piperazine- d 5 preparation of

[0055] 4-Ethyl-1-Boc-piperazine- d 5 (1.50 g, 7 mmol) dissolved in CH 2 Cl 2 (15 mL), to which was added CF 3 COOH (0.62 mL, 8.4 mmol), stirred at room temperature for 10 min, concentrated under reduced pressure to remove CH2 Cl 2 , to which CH 3 OH (10mL), concentrated under reduced pressure again to remove CH 3 OH, 0.79 g yellow oil crude product 1-ethyl-piperazine- d 5 , the yield was 95%, and could be directly used in the next step without further purification. ESI-MS (m / z): 120.1 (M+H) +1 , 1 HNMR (400 MHz, CDCl 3 ): δ =5.1 (1H, br s), 3.51-3.75 (8H, m).

example 3

[0056] Example 3: Ethyl 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(4-ethyl-1-piperazinyl)-3-quinolinecarboxylate- d 5 Preparation (coupling method)

[0057] 1-Ethyl-piperazine- d 5 (0.79 g, 6.7 mmol), ethyl 1-cyclopropyl-7-chloro-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (1.6 g, 5 mmol), Cs 2 CO 3 (3.3 g, 10 mmol), Pd(dba) 3 (0.1 g, 0.1 mmol) and BINAP (0.1 g, 0.15 mmol) were dissolved in DMF (20 mL), N 2 protection, stirred at 115°C for 2 h, after the reaction was completed, concentrated under reduced pressure to remove most of the solvent, and added CH 2 Cl 2 (20 mL), filtered through a sand core, and the filtrate was concentrated under reduced pressure to obtain a brownish-red oily crude product, which was subjected to silica gel column chromatography (CH 3 OH) to obtain 1.8 g of light yellow solid 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(4-ethyl-1-piperazinyl)-3-quinolinecarboxylic acid ethyl ester- d 5 , the yield is 93%. ESI-MS (m / z): 393.1 (M+H)...

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Abstract

The invention discloses a preparation method for enrofloxacin-d5. The preparation method comprises the following steps: performing a Buchwald-Hartwig coupling reaction on 1-ethyl-piperazine-d5 and 1-cyclopropyl-7-chloro-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic ethyl ester, and preparing 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(4-ethyl-1-piperazinyl)-3-quinoline carboxylic ethyl ester-d5; and after alkaline hydrolysis, to obtain the enrofloxacin-d5. The preparation method is capable of, through performing the coupling reaction on an esterified carboxylic group and ethyl piperazine, enabling a synthetic reaction to be more easily performed, the difficulty of the reaction is reduced, and a yield of products is very high. In addition, the isotope abundance can be guaranteed in the high-temperature reaction conditions, a reaction process is more easily controlled, the repeatability and the stability are higher, and the conditions of large-scale production are satisfied.

Description

technical field [0001] The present invention relates to a deuterated enrofloxacin- d 5 method of preparation. Background technique [0002] Enrofloxacin, also known as ethyl ciprofloxacin and enrofloxacin, is a third-generation synthetic quinolone antibacterial drug that was approved by the FDA on October 4, 1996. It has broad-spectrum antibacterial activity and strong Permeability, strong killing effect on Gram-negative bacteria, good antibacterial effect on Gram-positive bacteria, good oral absorption, high and stable blood concentration, can be widely distributed in tissues, and its metabolism The product is ciprofloxacin, which still has a strong antibacterial effect. It has strong antibacterial activity against almost all pathogenic bacteria in aquatic animals, and is currently designated as an animal-specific drug by the state. [0003] Stable isotope-labeled drugs are the same as their corresponding non-labeled drugs in terms of physical and chemical properties. ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/56C07B59/00
CPCC07B59/002C07D215/56C07B2200/05
Inventor 梁大伟王悦秋谭琳
Owner 雅安职业技术学院
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