Preparation for marbofloxacin key intermediate

A technology of marbofloxacin and intermediates, applied in the field of medicinal chemistry, can solve the problems of too long reaction route, expensive chemical reagents, unfavorable use and the like

Active Publication Date: 2015-12-09
WISDOM PHARM CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0016] In summary, the existing synthetic marbofloxacin key intermediate 6,7-difluoro-8-hydroxyl (or fluoro)-1-(methylamino)-4-oxo-1,4-dihydroquinone In the synthetic route of line-3-carboxylic acid (ester), there are various deficiencies, such as expensive chemical reagents, too long reaction route, use of chemical reagents that are unfavorable for suitability for industrialized production, etc. The inventors have studied and experimented, Invented a new key intermediate for the preparation of marbofloxacin, 6,7-difluoro-8-hydroxyl (or fluoro)-1-(methylamino)-4-oxo-1,4-dihydroquinoline- 3-carboxylate method

Method used

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  • Preparation for marbofloxacin key intermediate
  • Preparation for marbofloxacin key intermediate
  • Preparation for marbofloxacin key intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0030] Example 1: Preparation of 6,7,8-trifluoro-4-oxo-4-hydrogen-benzopyran-3-carboxylic acid ethyl ester (formula II, X=F, R=Et)

[0031] 3-(3,4,5-trifluoro-2-hydroxyphenyl)-3-keto-propionic acid ethyl ester (formula I, X=F, R=Et) (50g, 0.191mmol, 1.0eq), original A mixture of triethyl formate (85g, 0.574mmol, 3.0eq) and acetic anhydride (100g, 0.98mmol, 5.1eq) was heated in an oil bath until the system refluxed, and the refluxed state was kept for 24 hours. After the system cooled down, it was concentrated on a rotary evaporator, and the residue was added to ethyl acetate (1000L), and the obtained organic solution was washed twice with saturated sodium bicarbonate solution (2×200mL) and once with brine (100mL). Dry over sodium sulfate, filter out the desiccant, concentrate the obtained organic phase under reduced pressure, recrystallize the residue using a mixed solvent of ethyl acetate and heptane, and dry the product in vacuum at 60°C to constant weight to obtain a light ...

Embodiment 2

[0032] Example 2: Preparation of 6,7,8-trifluoro-4-oxo-4-hydrogen-benzopyran-3-carboxylic acid ethyl ester (formula II, X=F, R=Et)

[0033] 3-(3,4,5-trifluoro-2-hydroxyphenyl)-3-keto-propionic acid ethyl ester (formula I, X=F, R=Et) (50g, 0.191mmol, 1.0eq), original A mixture of triethyl formate (65g, 0.44mmol, 2.3eq) and acetic anhydride (78g, 0.76mmol, 4.0eq) was heated in an oil bath until the system refluxed, and the refluxed state was kept for 6 hours. After the system cooled down, it was concentrated on a rotary evaporator, and the residue was added to ethyl acetate (1000L), and the obtained organic solution was washed twice with saturated sodium bicarbonate solution (2×200mL) and once with brine (100mL). Dry over sodium sulfate, filter out the desiccant, and concentrate the obtained organic phase under reduced pressure. The residue is recrystallized with a mixed solvent of ethyl acetate and heptane, and the product is vacuum-dried at 60°C to constant weight to obtain a ...

Embodiment 3

[0034] Example 3: Preparation of 6,7-difluoro-8-hydroxyl-4-oxo-4-hydrogen-chromene-3-carboxylic acid methyl ester (formula II, X=OH, R=Me)

[0035]3-(4,5-difluoro-2,3-dihydroxyphenyl)-3-keto-propionic acid methyl ester (formula I, X=OH, R=Me) (50g, 0.20mmol, 1.0eq), A mixture of trimethyl orthoformate (51g, 0.48mmol, 2.4eq) and acetic anhydride (105g, 1.03mmol, 5.1eq) was heated in an oil bath until the system refluxed, and the refluxed state was kept for 12 hours. After the system cooled down, it was concentrated on a rotary evaporator, and the residue was added to ethyl acetate (1000L), and the obtained organic solution was washed twice with saturated sodium bicarbonate solution (2×200mL) and once with brine (100mL). Dry over sodium sulfate water, filter out the desiccant, concentrate the obtained organic phase under reduced pressure, recrystallize the residue using a mixed solvent of ethyl acetate and heptane, and dry the product in vacuum at 60°C to constant weight to obta...

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Abstract

The invention relates to preparation for a marbofloxacin key intermediate, and concretely relates to preparation of 6,7-difluoro-8-hydroxy(or fluoro)-1-methylamino-4-oxo-1,4-dihydroquinoline-3-carboxylate, and the key step relates to direct condensation of methylhydrazine and 6,7-difluoro-8-hydroxy(or fluoro)-4-oxo-4-hydro-benzypyran-3-carboxylate.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry and relates to a preparation method of a key intermediate of marbofloxacin. Background technique [0002] Marbofloxacin (Marbofloxacin) is a veterinary fluoroquinolone antibacterial drug, the chemical name is 9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-2, 3-dihydro-7H-pyridine[3,2,1-ij][4,1,2]benzoxadiazine-6-carboxylic acid, first developed by Roche, and manufactured by Vetoquinol (France) The company developed it further and launched it in Europe in 1995. Marbofloxacin is another third-generation quinolone antibacterial drug following Enrofloxacin, Danofloxacin, Sarafloxacin, etc., which has a wide range of antibacterial activities and has Very good kinetic characteristics, strong bactericidal power, fast absorption, wide distribution in the body, no cross-resistance with other antibacterial drugs, easy to use, and small adverse reactions. Pharmacokinetic studies have shown that mar...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/58
CPCC07D215/58
Inventor 邱小龙刘国柱王东辉胡林邓贤明游正伟江中兴邹平
Owner WISDOM PHARM CO LTD
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