JPS61246188A - Pyrido-1,4-benzoxazine derivative - Google Patents

Abstract

NEW MATERIAL:9, 10-Difluoro-3-methyl-7-oxo-2, 3-dihydro-7H-pyrido[1, 2,3- de]-1,4-benzoxazine-6-carboxylic acid and its lower alkyl ester. USE:An intermediate for ofloxacin, an antibacterial agent. PREPARATION:For example, 2,3,4-trifluoronitrobenzene is reacted with a strong base such as potassium hydroxide, etc., in a solvent such as dimethyl sulfoxide, etc., to give a compound shown by the formula I, which is reacted with monochloroacetone in the presence of potassium iodide and catalytically reduced to give a compound shown by the formula II. Then, it is reacted with a dimethylaminomethylenemalonic ester under heating to give a compound shown by the formula III, which is heated in polyphosphoric acid or its ester to give a compound shown by the formula IV and the ester part is hydrolyzed.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides 9,10-difluoro-3-methyl-7-o-2,3-dihydro-7H-pyrido [1,2,3-
Regarding del-1,4-benzoxazine-8-carboxylic acid and its lower alkaline ester, these are ofloxacin (9-fluoro-3-methyl-10-(4-methyl-1- piperazinyl)-7-oxo-2,3-dihydro a-7) 1-pyrido[+, 2,3-del-1,4-benzoxazine-
Useful for local pump manufacturing.

The method for producing the compound of the present invention is as follows.

That is, when 2,3.4-triple olonitrobenzene is stirred at room temperature in a solvent such as dimethyl sulfoxide or sulfolane in the presence of a strong base such as potassium hydroxide or sodium hydroxide, the fluorine atom at the ortho position of the nitro group is dissolved. is selectively hydrolyzed to produce 2,3-difluoro-6-ditrophenol in good yield. This compound is reacted with monochloroacetone in the presence of a catalytic amount of potassium iodide using potassium carbonate or sodium carbonate as a deoxidizing agent, and the resulting intermediate is reacted in the presence of a catalyst such as Raney nickel or palladium on charcoal. Catalytic reduction under pressure forms an oxazine ring, resulting in the formation of 7,8-difluoro-3-methyl-2,
3-dihydro-4H-1,4-benzoxazine can be obtained in good yield. This compound remains as a free base;
Alternatively, when used as an inorganic acid salt (e.g. salt salt) with dimethylaminomethylene malonic acid ester, the yield is high and 7.8-difluoro-3-methyl-2,3-dihydro-
4H-1,4-benzoxazin-4-yl)methylene malonic acid ester can be obtained. When this compound is heated in polyphosphoric acid or its ester, a ring-closing reaction occurs.
,3-del-1,4-pendyl-6-carboxylic acid ester is obtained, and when this is treated in an acid or base, the carboxylic acid ester is hydrolyzed to form e,10-
Difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-del-1,4-benzoxazine-local phosphoric acid is obtained.

When this compound is heated and reacted with N-methylpiperazine, ofloxacin can be obtained in high yield (JP-A-57-4
H86 and JP-A-58-72588) Example 2.3.4- Trifluoronitrobenzene 20g Q
Dissolve in 100 ml of dimethyl sulfoxy F, 18-20
85 ml of 202 hydroxide solution was added dropwise at 0.degree. C. and stirred for 5 hours at the same temperature.To the reaction mixture, 500 ml of water was added and shaken with chloroform. The aqueous layer is separated, acidified with hydrochloric acid, and extracted with chloroform. The extract was washed with water and dried with Glauber's salt, and the chloroform was distilled off to obtain 18.9 g of 2.3-difluoro-6-nitrophenol with a melting point of 81°C.
(85.5$) was obtained.

Elemental analysis value Cb) 13 F2 NO: Closing and weighing @ C41, 18, H1, 73, N 8.00 analysis f
fi C40,95, H1,75, N 8.22 5.8 g of the above compound, 5.0 g of monochloroacetone, 8.0 g of potassium carbonate and potassium iodide Q, 8. was added to acetone 1001 and refluxed for 4 hours. Cold welding, insoluble matter was filtered off, the solvent was distilled off, the residue was dissolved in benzene, and after washing with water,
Dry with Glauber's salt. The solvent was distilled off to give 2-acetonyloxy-3,4-difluoronitrobenzene as an oil.8.
2 g (81,1) $) was obtained.

Elemental analysis value C9H7F2 Total x value as NO4 C4
f1.78. l(3,05,118,08 analysis value 0
4B, 49. H2,98,N 5.95 Compound 5 above
．． 0g was dissolved in 50ml of ethanol, Tenay Nickel 51 was added thereto, and catalytic reduction was carried out at normal pressure. After the theoretical amount of hydrogen has been absorbed, the catalyst is filtered off and the solvent is completely distilled off. The residue was dissolved in benzene and shaken with 6z hydrochloric acid to give 7,8-difluoro-3-methyl-2,3-dihydro-4H-1,4
- Benzoxazine hydrochloride precipitated and was collected by filtration. Melting point 182-185°C 3.5g (73.2$).

Add 2.0 g of the above hydrochloride and 2.5 g of diethyl dimethylaminomethylene malonate to 20 ml of glacial butyric acid,
Stir at 30°C for 5 hours. The solvent was distilled off under reduced pressure, the residue was purified by silica gel promatography, and the fraction eluted with benzene-chloroform (3:2) was obtained as an oil (
7,8-difluoro-3-methyl-2,3-dihydro-
2.4 g (74.8%) of diethyl 4H-1,4-benzodin-4-yl]methylenemalonate was obtained.

Elemental analysis value Calculated value as C++H+qF2NOs
C57,48,H5,39,N 3.94 analysis value C5
7,15,H5,35,N 3.91 Above compound 2.0
Add g to 20 g of ethyl polyphosphate and heat to 140-145℃
The reaction mixture was stirred for 1.5 hours and poured into water ice, and the precipitate was extracted with chloroform. The extract was washed with a 5z aqueous potassium carbonate solution and then with water, dried with mirabilite, and the solvent was distilled off to give 9.10-difluoro-3-methyl-7-, which has a melting point of 261°C.
Oxo-2,3-dihydrof H-pyrido[1,2,3
-del-1,4-henzoxazinetocarboxylic acid ethyl Jl/1.30 g (74, fl$) was obtained.

Calculated value as elemental analysis value C+sH+xF2NOz
C58,25,H4,24,N 4.53 analysis value C,
58, +8. H4,33,N 4.38 Compound 2 above
．． Dissolve 0g in 25ml of concentrated hydrochloric acid-acetic acid (1:4),
Reflux for an hour. After cold welding, the precipitated crystals are collected by filtration, washed with water, ethanol, and ether in that order, and dried.
．． 10-difluoro-3-methylrea-oxo-2,
3-dihydro-7H-pyrido [1,2,3-del-
1,4-Hen 7'+ f shear 8- Carphonic acid 1
．． 62g (89%) was obtained.

Claims (1)

[Claims] 9,10-difluoro-3-methyl-7-oxo-2,
3-dihydro-7H-pyrido[1,2,3-de]-1
, 4-benzoxazine-6-carboxylic acid and its lower alkyl ester