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Preparation method of balofloxacin dihydrate

A technology for baloxacin dihydrate and compounds, which is applied in the field of preparation of baloxacin dihydrate, can solve the problems of poor stability of acetyl boric acid chelates, etc., and achieve simple operation, high total yield, and improved The effect of product quality

Inactive Publication Date: 2013-05-15
ZHEJIANG APELOA KANGYU PHARMA +1
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  • Abstract
  • Description
  • Claims
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AI Technical Summary

Problems solved by technology

[0011] Compared with the previous direct reaction of quinolonic acid with side chain amine, the reaction conditions of this route are milder, easier to control, higher yield (70-78%) and easier to purify the final product, but the acetylboronic acid chelate of formula 7 quinolonic acid The compound is less stable during the reaction

Method used

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  • Preparation method of balofloxacin dihydrate
  • Preparation method of balofloxacin dihydrate
  • Preparation method of balofloxacin dihydrate

Examples

Experimental program
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Effect test

Embodiment 1

[0039] The synthesis circuit of the present embodiment is basically:

[0040]

[0041] The compound of formula 2 (15g, 33.26mmol) was dissolved in 60mL of acetonitrile, triethylamine (18mL, 129.14mmol) and 3-methylaminopiperidine dihydrochloride (6.5g, 34.74mmol) were added once at room temperature, and the temperature was kept at 30 ~35°C. After reacting for 12 hours, acetonitrile was recovered by distillation under reduced pressure to obtain 28.9 g of crude yellow compound. The crude yellow compound was directly used in the next reaction. The yellow compound analysis sample was purified by column chromatography and detected as the compound of formula 3. ESI-MS m / z: 546[M+H] +1 . H-NMR (CDCl 3 )δ: 1.02(6H, t), 1.3-1.26(2H, t), 1.34-1.43(2H, m), 1.75-1.85(1H, m), 1.90-2.04(2H, m), 2.35-2.41( 4H, m), 2.43-2.53(1H, m), 2.73(3H, s), 3.26-3.32(2H, m), 3.53-3.59(2H, t), 3.77(3H, s), 3.97-3.99( 1H, d) 4.21-4.26(1H, m), 7.97(1H, d), 9.14(1H, s).

[0042] Add 9 g of sodium ...

Embodiment 2-6

[0045] Using the same reaction conditions as in Example 1, 5 batches of baloxacin dihydrate were prepared.

[0046] Table 2 Compound of Formula 2 Preparation of Compound of Formula 1 through Intermediate Compound of Formula 3 Results List

[0047]

[0048] Note: The dosage of the compound of formula 5 is 6.7g, the dosage of triethylamine is 18mL, and the dosage of acetonitrile is 60mL.

Embodiment 7

[0051] The compound of formula 2 (15g, 33.26mmol) was dissolved in 60mL DMF, triethylamine (18mL, 129.14mmol) and 3-methylaminopiperidine dihydrochloride (6.5g, 34.74mmol) were added once at room temperature, and the temperature was kept 30-35°C, reacted for 12 hours, and recovered DMF by distillation under reduced pressure to obtain 35.5 g of crude yellow compound, which was directly used in the next reaction.

[0052] Add 100mL aqueous solution of 9g sodium hydroxide to the crude compound of formula 3, slowly raise the temperature to 65-70°C and react for 2.5h, the reaction solution is cooled to room temperature, filtered, the filtrate is adjusted to pH 7.5 with 4M hydrochloric acid, stirred at room temperature for 1h, cooled to 4°C, let stand overnight, and filter. Add 100mL of 7% acetic acid to the obtained solid, stir at room temperature for 2h, filter, adjust the pH of the filtrate to 7.5 with 10% aqueous sodium hydroxide solution, stir at room temperature for 2h, cool t...

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Abstract

The invention relates to the field of compound synthesis and particularly relates to a preparation method of balofloxacin dihydrate. The method comprises the following steps of: reacting 1-cyclopropyl-6, 7-difluoro-1, 4-dihydro-8-methoxyl-4-oxoquinoline-3-carboxylate radical-O<3>, O<4>-dipropionate boron as an intermediate with side chain 3-methylamino piperidine to generate 1-cyclopropyl-6-fluorine-1, 4-dihydro-8-methoxyl-7-(3-methylamino piperidine-1-radical)-4-oxoquinoline-3-carboxylate radical-O<3>, O<4>-dipropionate boron, and then hydrolyzing boric acid chelate, thus preparing the balofloxacin dihydrate. Compared with the traditional method, the preparation method has the advantages that the intermediate is more reliable and the yield is higher, and therefore the preparation method has a more industrial production prospect.

Description

technical field [0001] The invention relates to the field of synthesis of fluoroquinolone antibacterial drugs, in particular to a preparation method of baloxacin dihydrate. Background technique [0002] Baloxacin, chemical name: 1-cyclopropyl-7-(3-methylamino-1-piperidinyl)-8-methoxy-6-fluoro-1,4-dihydro-4-oxo -3-quinolinecarboxylic acid, a compound shown in formula 4, [0003] [0004] It is a fluoroquinolone antibacterial drug. It is mainly used for the treatment of Staphylococcus, Streptococcus, Enterococcus, Morganella, Escherichia coli, Prufidenia, Citrobacter, Klebsiella pneumoniae, Enterobacter, Serratia, Proteus, Pseudomonas, Uncomplicated urinary tract infections caused by sensitive bacteria such as Peptostreptococcus, such as cystitis, urethritis, etc. [0005] The traditional synthesis process of baloxacin is as follows: [0006] The synthetic method of the baloxacin dihydrate reported in the patent EP0342675 is: [0007] [0008] This method uses quino...

Claims

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Application Information

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IPC IPC(8): C07D401/04
Inventor 张柯华陈喆冯立春杨平爱张春生郭振荣
Owner ZHEJIANG APELOA KANGYU PHARMA
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