JPS61143364A - Production of quinolonecarboxylic acid derivative - Google Patents

Abstract

PURPOSE:To obtain the titled substance useful as an intermediate for synthesizing a compound useful as an antimicrobial agent simply in highyield, by using a novel aniline as a raw material, and subjecting the reaction product of the aniline and an alkoxymethylene malonic acid dialkyl ester to ring formation. CONSTITUTION:A novel compound shown by the formula [X and Y are halogen; Z is group shown by the formula II or formula III; R<1> and R<2> are H, or lower alkyl; R<3> is H, lower alkyl, lower acyl, lower alkoxycarbonyl, etc.; R<4> is H, lower alkyl, etc.; R<5> is H, lower alkyl, etc., or R<4> and R<5> may be phthaloyl) is reacted with an alkoxymethylene malonic acid dialkyl ester or a mixtutre of an orthofomic ester and a malonic acid dialkyl ester under heating at 60-200 deg.C, preferably aat 100-160 deg.C. Then, the reaction product shown by the formula IV (R is lower alkyl) is subjected to ring formation, to give a compound shown by the formula V. The compound shown by the formula I is synthesized from a compound shown by the formula VI.

Description

[Detailed Description of the Invention] [Industrial Application Field] The present invention is expected to be used as an antibacterial agent (in the formula,
X and Y are each the same or different; R1 and R2 are each hydrogen or lower alkyl; Re and R7 are hydrogen or lower alkyl;

p-nitrobenzyl or p-aminobenzyl.

R8 is hydrogen or lower alkyl. ), hydrates thereof, and salts thereof.

[Problem that the invention seeks to solve]

- The quinolone carboxylic acid derivative represented by the general formula IV) is a novel compound synthesized for the first time by the present inventors, and has high antibacterial activity.

Examples of methods for producing these compounds include the following methods.

(R'-H, CH3) The present invention relates to a method for producing such a compound, and is a novel production method aimed at improving the yield and simplifying the operation.

[Means for solving problems]

Quinolone carbon R represented by the general formula (IV)
The derivative can be produced by the method shown below.

First, general formula (I) (wherein X and Y are each the same or different,
R1 and R2 are each hydrogen or lower alkyl R3
is hydrogen, lower alkyl, lower acyl, lower alkoxycarbonyl, p-nitrobenzyl or p-aminobenzyl which may be substituted with an acyl group; R4 is substituted with hydrogen, lower alkyl, p-nitrobenzyl or an acyl group; Good p-aminobenzyl.

R5 is hydrogen, lower alkyl, lower acyl or lower alkoxycarbonyl. Furthermore, R4 and R5 may be phthaloyl. ) Anilines and alkoxymethylene malonic acid dialkyl esters, for example, 1 to 5 equivalents, preferably 1
A mixture of ~1.5 equivalents of ethoxymethylene malonic acid diethyl ester or orthoformate and malonic acid diester is heated at 60~200°C, preferably at 100~1
By heating to 60°C, a compound represented by general formula (II) (wherein X, Y, Z and R are the same as above) is produced. During the reaction, it is also preferable for the reaction to proceed by blowing inert gas such as nitrogen gas to remove the generated alcohol from the system. Then the general formula (
The compound represented by II) is cyclized. Such cyclization reactions can be carried out using suitable catalysts such as aluminum chloride, titanium trichloride.

In the presence of Lewis acids such as boron trifluoride, or polyphosphoric acid, polyphosphoric acid ester, etc., without a solvent or with a solvent such as diphenyl ether or carbon tetrachloride.

It is carried out using carbon disulfide, nitrobenzene, nitromethane, etc. The reaction temperature is appropriately selected from 0°C to 250°C or from 0°C to the boiling point of the solvent. As a preferable example using polyphosphoric acid, the compound represented by the general formula (I) is added to 1 to 100 times the amount of polyphosphoric acid, preferably 5 to 20 times the amount, and the mixture is heated at room temperature to 200°C, preferably 80 to 14°C.
This is easily carried out by heating at 0° C. for 5 minutes to 20 hours, preferably 10 minutes to 1 hour. The compound represented by the general formula [°m] (wherein X, Y, Z and R are the same as above) obtained here can be easily converted to the general formula (IV) (in the fog , X, Y and Z' are the same as above).

Hydrolysis can be carried out by commonly known methods with acids or alkalis. Moreover, the general formula (I[
The back of the compound represented by [), R3 and R5 in Z
is lower acyl, lower alkoxycarbonyl, or R
In the compound where 4 and R5 are phthaloyl, only the ester group is hydrolyzed to give the general formula (V), where X and Y are the same as above. R1 here! and O R is lower acyl or lower alkoxycarbonyl, and R1, R2 and R4 are the same as above. Kame, R4 and R may be phthaloyl.

After isolation and purification as a compound represented by formula (IV), it can be further hydrolyzed to convert it into a compound represented by general formula (IV).

Also, a compound with the general formula CI [[) in which R3 and R4 in 2 are p-nitrobenzyl, and a compound with the general formula (rV),
A compound in which R6 and R7 in 2' are p-nitrobenzyl can each be reduced by a conventional method and converted into a compound in which R6 and R7 are p-nitrobenzyl.

The anilines represented by the general formula (I), which are the starting materials of the present invention, are also new compounds, and are produced, for example, by the following method.

(Example〕 The present invention will be explained below with reference to Examples.

Example 1 Synthesis of N-cyclopropyl-N-(3-<4-ethoxycarbonyl-1-piperazinyl)-2,4-difluorophenylcoaminomethylene diethyl malonate N-cyclopropyl-3-(4-ethoxycarbonyl −
220 mg of 1-piperazinyl) -2,4-difluoroaniline and 160 m'j of diethyl ethoxymethylenemalonate were mixed and heated on an oil bath at 140 to 150°C for 2 hours.
Stir for hours. Cold welding, the reaction product was subjected to preparative a-layer chromatography (ethyl acetate-hexane).

1:3) to obtain the desired product 251 as a pale brown oil.
rItg (yield 75%) was obtained.

Example 2 N-cyclopropyl-7-(4-ethoxycarbonyl-
Synthesis of ethyl 1-piperazinyl) -6,8-difluoro-1゜4-dihydro-4-oxo-3-quinolinecarboxylate a) N-cyclopropyl-3-(4-ethoxycarbonyl-1-piperazinyl) - 0.73 g of 2,4-difluoroaniline (J) and 0.53 g of diethyl ethoxymethylene malonate were mixed and stirred for 4 hours on an oil bath at 140 to 150°C.Cold welding, 8.0 g of polyphosphoric acid was added to the reaction product.
After stirring on an oil bath at 110 to 115°C for 30 minutes, ice chips were added and extraction was performed with chloroform. The organic layer was washed sequentially with water, an aqueous potassium carbonate solution, and water, dried over anhydrous sodium sulfate, and concentrated. The residue was recrystallized from 10 d of ethanol to obtain 0.46 g of the desired product as pale brown prism crystals (yield: 43
．． 5%).

Melting point 169-170℃ Elemental analysis value (%): Cz2Hzs F2 N! O
5. Calculated value as Et OH C: 58.47 H: 5.97 N:
8.89 Actual value C: 58.28) 1:
5゜91 N: 8.89b) 16゜89 g of N-cyclopropyl-3-(4-ethoxycarbonyl-1-piperazinyl)-2,4-difluoroaniline and 12.4SF of diethyl ethoxymethylenemalonate were mixed together and 140 Stirred on oil bath at 0C for 18 hours. After cold welding, 170 g of polyphosphoric acid was added to the reaction mixture, stirred for 30 minutes on an oil bath at 110-115°C, poured into 500 Id ice water, the precipitate was collected by filtration, and recrystallized from ethanol to form cream-colored prism crystals. Target product 15.83 g (yield 64.5%
) was obtained. Melting point 169-170℃ Elemental analysis value (%)
: C2ZH2S F2 N30S ・niEt OH
Calculated values as C: 58.47 H: 5.97 N:
8.89 Actual value C: 58,48 H: 5,
92 N,: 9,02 Example 3 1-Cyclopropyl-1-(4-ethoxycarbonyl-
1-piperazinyl) -6,8-difluoro-1,4
-Synthesis of dihydro-4-oxo-3-quinolinecarboxylic acid 1-cyclopropyl-7-(4-ethoxycarbonyl-
1-piperazinyl) -6,8-difluoro-1,4
-Dihydro -200q of ethyl 4-oxo-3-quinolinecarboxylate was added to 5ai of concentrated hydrochloric acid! , ethanol 5IIdl
The mixture was added to a mixed solution of 5- and water, and refluxed for 3 hours while stirring. The reaction solution was cooled in a water bath, and the precipitated crystals were collected by filtration to obtain 130 mg (yield: 72.9%) of the desired product as colorless needle crystals. Melting point 221-222℃ Elemental analysis value (%):
Calculated value as CZON21 F2 N30S C:57
．． 00 H: 5.02 N: 9.97 Actual value C: 56.89 H: 4,81 N:
9.87 Example 4 1=cyclopropyl-6,8-difluoro-1,4-
Dihydro-4-oxo-7-(1-perazinyl)-
Synthesis of 3-quinoline carbon n pear 1-cyclopropyl-7-(4-ethoxycarbonyl-
1-piperazinyl) -6,8-difluoro-1,4
-Dihydro-4-oxo-3-quinolinecarboxylic acid ethyl 15.8g was added to 30g of 1N sodium hydroxide aqueous solution.
0d and stirred for 3 hours on a 100°C oil bath. The reaction solution was cooled in a water bath, adjusted to I)H6 with acetic acid, and then heated to 5°C.
I left it for 2 days. The precipitated crystals were collected by filtration and washed sequentially with UDMF and ethanol to obtain 11.0 g of the desired colorless prism crystals.
(yield 91.8%). Melting point 278-281℃ Elemental analysis value (%): Ctr Her Fz N30
3. As 4HzO

Claims (2)

[Claims] (1) General formula [I] ▲There are mathematical formulas, chemical formulas, tables, etc.▼[I] (In the formula, X and Y each represent the same or different halogens, and Z is ▲There are mathematical formulas, chemical formulas, tables, etc.▼ or ▲There are mathematical formulas, chemical formulas, tables, etc.▼ Here, R^1 and R^2 are each hydrogen or lower alkyl, and R^3 is hydrogen, lower alkyl, lower acyl, lower alkoxycarbonyl, p-nitrobenzyl. or p-aminobenzyl which may be substituted with an acyl group, R^4 is hydrogen, lower alkyl, p-nitrobenzyl or p-aminobenzyl which may be substituted with an acyl group, R^5 is hydrogen, lower Alkyl, lower acyl or lower alkoxycarbonyl. Also, R^
4 and R^5 may be phthaloyl. ) is reacted with alkoxymethylene malonic acid dialkyl ester or orthoformic acid ester and malonic acid dialkyl ester, and the general formula [II] ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [II] (In the formula, R is General formula [III] ▲There are mathematical formulas, chemical formulas, tables, etc.▼[III] ( A method for producing a quinolone carboxylic acid compound represented by the formula (wherein X, Y, Z and R are the same as above). (2) General formula [IV] characterized by hydrolyzing the quinolone carboxylic acid compound represented by the general formula [III] described in claim 1 ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [IV ] (In the formula, X and Y each represent the same or different halogen, and Z' represents R^6-NN- or ▲There are mathematical formulas, chemical formulas, tables, etc.▼.Here, R^1 and R^2 are each hydrogen or lower alkyl, R^6 and R^7 are hydrogen, lower alkyl, p-nitrobenzyl or p-aminobenzyl, R^8 is hydrogen or lower alkyl) and their water Method for producing Japanese products and their salts