Preparation method of ofloxacin

A technology of ofloxacin and compounds, applied in the field of preparation of ofloxacin, can solve the problems of reduced yield, reduced content of final products, long chemical synthesis routes, etc.

Active Publication Date: 2013-10-23
TOPFOND PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In the above process route, because the chemical synthesis route is long, and the unreacted intermediates are easy t

Method used

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  • Preparation method of ofloxacin
  • Preparation method of ofloxacin
  • Preparation method of ofloxacin

Examples

Experimental program
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Effect test

Embodiment 1

[0024] 1) Preparation of formula (V) compound

[0025] 300g of toluene, 35.5g of formula (III), and 17g of L-aminopropanol were successively put into a 500ml three-necked bottle, stirred and heated to 20°C, and timed to keep warm. After 8 hours of heat preservation, 8.5g of liquid ammonia and 60g of trimethylchlorosilane were added, and the temperature was kept at 50°C for 4 hours. It can be directly used in the next step without separation.

[0026] 2) preparation of formula (VIII) compound

[0027] The temperature of the toluene solution of formula (V) in the previous step is raised to 50°C, and it is stirred and dropped into formula (VI) for 3-4 hours. The formula (VII) is prepared by keeping the temperature at 50-100°C for 4 hours after dropping. Add 200ml of water, add hydrochloric acid to adjust the pH to <7.0, separate the water layer, recover toluene under reduced pressure, keep the temperature <90°C, and vacuum <-.09MPa. Stop when no toluene flows out, and the res...

Embodiment 2

[0037] 1) Preparation of formula (XII) compound

[0038] 300g of toluene, 35.5g of formula (III), 17g of D, L-aminopropanol were put into a 500ml three-necked bottle in sequence, stirred and heated to 40°C, and timed to keep warm. After 6 hours of heat preservation, 75g of triethylamine and 60g of trimethylchlorosilane were added, and the temperature was kept at 50°C for 4 hours. It can be directly used in the next step without separation.

[0039] 2) Preparation of formula (XIV) compound

[0040] The temperature of the toluene solution of formula (XII) in the previous step is raised to 50°C, and it is stirred and dropped into formula (VI) for 3-4 hours. The formula (XIII) was prepared by keeping the temperature at 30-60°C for 4h after dropping. Add 200ml of water, add hydrochloric acid to adjust the pH to 7.0, separate the water layer, recover toluene under reduced pressure, keep the temperature <90°C, and vacuum <-.09MPa. Stop when no toluene flows out, and the residue i...

Embodiment 3

[0050] 1) Preparation of formula (V) compound

[0051] 300g of toluene, 35.5g of formula (III), and 17g of L-aminopropanol were successively put into a 500ml three-necked bottle, stirred and heated to 50°C, and timed to keep warm. After 4 hours of heat preservation, 20 g of ether, 15 g of ethanol, 25 g of ethanethiol, and 60 g of trimethylchlorosilane were added, and the mixture was kept at 50° C. for 4 hours. It can be directly used in the next step without separation.

[0052] 2) preparation of formula (VIII) compound

[0053] The temperature of the toluene solution of formula (V) in the previous step is raised to 50°C, and it is stirred and dropped into formula (VI) for 3-4 hours. The formula (VII) is prepared by keeping the temperature at 50-100°C for 4 hours after dropping. Add 200ml of water, add hydrochloric acid to adjust the pH to <7.0, separate the water layer, recover toluene under reduced pressure, keep the temperature <90°C, and vacuum <-.09MPa. Stop when no t...

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Abstract

The invention provides a preparation method of ofloxacin. The preparation method comprises the following steps of: reacting (N,N)-dimethylamino ethyl acrylate with aminopropanols in methylbenzene; directly adding lewis base serving as a catalyst and trimethylchlorosilane to protect hydroxyl and amido; after reaction is completely finished, dropwise adding (2,3,4,5)-tetrafluorobenzoyl chloride; preserving heat; performing acid washing; removing protecting groups; concentrating an organic layer to obtain an oil layer; adding a proper amount of dimethyl formamide (DMF); diluting and dropwise adding backflow DMF having anhydrous potassium fluoride; recovering DMF and adding water to centrifuge; adding acid water into a solid to hydrolyze to obtain difluorocarboxylic acid; and completely reacting difluorocarboxylic acid and N-methyl piperazine in dimethylsulfoxide (DMSO) by using triethylamine as an acid-binding agent at 90-100 DEG C to obtain ofloxacin. According to the process, hydroxyl and amido are protected by using trimethylchlorosilane, so that the utilization degree of (2,3,4,5)-tetrafluorobenzoyl chloride is effectively increased, and the generation of impurities is reduced to ensure that the reaction yield of intermediate difluorocarboxylic acid is increased by 10 percent.

Description

technical field [0001] The invention relates to a preparation method of medicine, in particular to a preparation method of ofloxacin. Background technique [0002] Fluoroquinolones have achieved great success in clinical anti-infection treatment due to their high-efficiency, spectrum, and low-toxicity antibacterial properties. The synthesis routes of levofloxacin reported in the literature mainly include the following three types: [0003] 1. The early route is mostly split method: including high performance liquid phase split EP206283 (1986) and enzyme split method (K, Sakano, Aina Biol.chem.: 1987,51,1265), but the split method is not suitable for Industrial production; [0004] 2. Prepared from trifluoronitrobenzene as the starting material, EP273399(1988), EP36841(1990); [0005] 3. Levofloxacin US4777253 (1988) was prepared from tetrafluorobenzoic acid as the starting material through 7 steps. [0006] Among them, route 3 is the most commonly used method for industri...

Claims

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Application Information

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IPC IPC(8): C07D498/06
CPCY02P20/55
Inventor 杨朱红杨秋燕陈强王媛王志华张卫民韩德全吴戈亮王九焦国华
Owner TOPFOND PHARMA CO LTD
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