A deuterated enrofloxacin-d 5 preparation method

A deuterium enrofloxacin, -d5 technology, applied in the direction of organic chemistry methods, chemical instruments and methods, isotope introduction of heterocyclic compounds, etc., can solve the problem of not being able to obtain isotope abundance, etc., to reduce the difficulty of the reaction, the reaction Easy process, high reproducibility and stable results

Active Publication Date: 2022-02-25
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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  • A deuterated enrofloxacin-d <sub>5</sub> preparation method
  • A deuterated enrofloxacin-d <sub>5</sub> preparation method
  • A deuterated enrofloxacin-d <sub>5</sub> preparation method

Examples

Experimental program
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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 (10 mL), 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 deuterated enrofloxacin- d 5 The preparation method, the preparation method is 1-ethyl-piperazine- d 5 1-cyclopropyl-7-chloro-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester occurs Buchwald-Hartwig coupling reaction to prepare 1-cyclopropyl- 6‑Fluoro‑1,4‑Dihydro‑4‑Oxy‑7‑(4‑Ethyl‑1‑Piperazinyl)‑3‑Ethyl quinolinecarboxylate‑ d 5 ; Then obtain deuterated enrofloxacin after alkaline hydrolysis‑ d 5 . The preparation method of the present invention carries out the coupling reaction with ethylpiperazine after esterification of the carboxylic acid group, which can make the synthesis reaction easier to carry out, the reaction difficulty is reduced, and the product has a very high yield. The isotope abundance can also be guaranteed, the reaction process is easier to control, the reproducibility and stability are higher, and the conditions for large-scale production are met.

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 Patents(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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