Preparation method of gemifloxacin side chain compound

A technology of gemifloxacin and compounds, applied in the field of preparation of gemifloxacin side chain compounds, can solve the problems of unfavorable industrial production, unfavorable industrial production, long route, etc., and achieve the effect of low cost, easy realization and simple process

Active Publication Date: 2021-12-10
北京阳光诺和药物研究股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] This route includes 5 steps of chemical reactions. The starting material N-tert-butoxycarbonyl-4-cyano-3-pyrrolidone needs to be reduced by Raney nickel and palladium carbon in two steps. The reduction pressure is above 4Mpa, which is not conducive to industrial production.
[0015] In summary, the existing synthetic techniques all have the disadvantages of long routes, low yields, and unfavorable industrial production. It is urgent to develop a new route to solve this problem.

Method used

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  • Preparation method of gemifloxacin side chain compound
  • Preparation method of gemifloxacin side chain compound
  • Preparation method of gemifloxacin side chain compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0058] Embodiment 1, the preparation of gemifloxacin side chain

[0059] (1) Synthesis of Compound V

[0060] Purchasing compound IV, take 105.0g compound IV, 50.1g (1.2eq) methoxyamine hydrochloride and 1000ml methanol into a 2L reaction flask, then add 47.5g (1.2eq) pyridine as catalyst, at 20~25°C React for 5h, TLC monitors the reaction, after the reaction is completed, distill to dryness under reduced pressure, add water and dichloromethane to separate layers, wash the organic phase with saturated sodium bicarbonate solution and saturated brine successively, dry over anhydrous sodium sulfate, and distill to dryness under reduced pressure , to obtain compound V (117.8 g, yield 98.4%).

[0061] The LC-Ms spectrum of compound V is as follows figure 1 shown.

[0062] (2) Synthesis of compound VI

[0063] Add 20g of compound V, 200ml of methanol and 3g of 10% palladium carbon into a stainless steel hydrogenation kettle, and react for 2h at 20-25°C under a hydrogen atmosphere ...

Embodiment 2

[0090] Embodiment 2, the preparation of gemifloxacin

[0091] Add 14.1 mg (5 mmol) of 1-cyclopropyl-7-chloro-6-fluoro-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylic acid and 15 ml of water into the reaction flask , add triethylamine, then dropwise add 10.8g (5mmol) of 4-aminomethyl-3-methoxyiminopyrrole prepared in Example 1, react at 20-25°C for 15 hours, filter, separate the precipitated solid and Drying gave 16.7 g (yield: 85%) of gemifloxacin (compound (III)).

[0092] The Ms collection of collection of collections, NMR collection of collection of collections and HPLC collection of collections of the compound (III) prepared in the present embodiment are respectively as follows Figure 6-Figure 8 shown.

[0093] Wherein, the detection condition of HPLC is as follows:

[0094] Chromatographic column: CAPCELL PAK C18 150×4.6mm×5um;

[0095] Injection volume: 20ul;

[0096] Temperature: 45°C;

[0097] Wavelength: 270nm;

[0098] Flow rate: 1.2ml / min;

[0099] Mobile ...

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Abstract

The invention discloses a preparation method of a gemifloxacin side chain compound. The preparation method comprises the following steps: S1, carrying out a reaction on 1-N-tert-butyloxycarbonyl-4-cyano-3-pyrrolidone and methoxyamine hydrochloride to obtain a compound as shown in a formula (V); S2, in an inert atmosphere, at a temperature of 10-50 DEG C, in the presence of palladium on carbon, and in a hydrogen atmosphere of 0.1-0.5 Mpa, carrying out a hydrogenation reduction reaction on the compound as shown in the formula (V) for 1-3 h; adding Boc anhydride, continuing the hydrogenation reduction reaction for 4-8 h under the conditions of 10-50 DEG C and 0.1-0.5 Mpa, and obtaining a compound shown in the formula VI; S3, enabling the compound shown in the formula VI to react with acid to remove the protecting group, and obtaining the gemifloxacin side chain compound shown in the formula I. The preparation method disclosed by the invention is simple in process, very mild in reaction condition and very easy to implement; (2) the raw materials are low in price and cost; (3) a novel and effective gemifloxacin side chain synthesis process route is created.

Description

technical field [0001] The invention relates to a preparation method of a gemifloxacin side chain compound, belonging to the technical field of drug synthesis. Background technique [0002] Gemifloxacin is a fourth-generation new fluoroquinolone antibacterial agent developed by Korea LG Chemicals, as shown in compound (III): 7-(4-aminomethyl-3-methoxyiminopyrrolidine-1- base)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylic acid, trade name Factive, has good curative effect, less toxic and side effects The advantages. [0003] [0004] Gemifloxacin is the first antibiotic approved for community-acquired pneumonia caused by multidrug-resistant Streptococcus pneumoniae strains (MDRSP). For the treatment of acute bronchitis, chronic bronchitis, upper respiratory tract infection caused by Streptococcus pneumoniae, methicillin-resistant Staphylococcus aureus, Haemophilus influenzae or Moraxella catarrhalis and pneumococcus, and Chlamydia pneumoniae Co...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/22
CPCC07D207/22Y02P20/55
Inventor 刘宇晶马昂罗桓张文腾张强赵隋红孙跃军袁伟锋童元峰谌宗永
Owner 北京阳光诺和药物研究股份有限公司
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