CN85101662A - The technology of preparation quinoline carboxylic acid derivative - Google Patents

Abstract

The invention relates to preparation has the technology of the antiseptic-germicide of important value.Especially about preparing the technology of quinoline carboxylic acid derivative.

Description

The technology of preparation quinoline carboxylic acid derivative

The invention relates to preparation 6,8-two fluoro-1-(2-fluoro ethyls)-1,4-dihydro-4-oxygen-7-(1-piperazine or 4-methyl isophthalic acid-piperazine)-3-quinoline carboxylic acid's technology, this compounds can be used as antiseptic-germicide, its chemical structure such as molecule formula IV

Here R ₁Be: hydrogen atom or methyl

Especially the technology of highly purified this class antiseptic-germicide of molecule formula IV of industrial production.Intermediate 6,8-two fluoro-1-(2-fluoro ethyls)-1,4-dihydro-4-oxygen-7-(1-piperazine or 4-methyl isophthalic acid-piperazine)-3-quinoline carboxylic acid alkyl ester (III) is by corresponding 6,8-two fluoro-7-halo-1-(2-fluoro ethyls)-1,4-dihydro-4-oxygen-3-quinoline carboxylic acid alkyl ester (I) and bridged piperazine derivatives (II) prepared in reaction.

Here R is: the low molecular weight alkyl of 1 to 3 carbon atom, X is: halogen atom.

The R here ₁Identical with the molecule formula IV.

Antiseptic-germicide (IV) is obtained by the intermediate compound hydrolysis of molecule formula III

The R here ₁With R and molecule formula I, the R of (II) ₁, R is identical.

Because our research, during industrial production antiseptic-germicide of the present invention, reached the product purity height, yield is good, handles the level of being easy to.

The concrete practice is, with the mixture heating up of 1 molar molecule formula I compound and 1 to 4 molar bridged piperazine derivatives (II) between the room temperature to 150 ℃, preferably between 40 to 120 ℃, can obtain the compound of molecule formula III, here can have, also can not have solvent or as the alkali of hydrogeneous acid acceptor.Operable alkali has in this reaction: pyridine, picoline (C ₆H ₇N), triethylamine etc., these organic basess also can be used as reaction solvent.In this reaction, can have: benzene, toluene, methyl-sulphoxide, dimethyl formamide, acetonitrile, spy-butanols etc. as the material of reaction solvent.

6,8-two fluoro-1-(2-fluoro ethyls)-1,4-dihydro-7-(4-methyl isophthalic acid-piperazine)-4-oxygen-3-quinoline carboxylic acid alkyl ester (III: R ₁=CH ₃) can be by 6,8-two fluoro-1-(2-fluoro ethyls)-1,4-dihydro-4-oxygen-7-(1-piperazine)-3-quinoline carboxylic acid alkyl ester (III: R ₁=H) and formaldehyde, and the reaction of reductive agent formic acid obtains.

When using acid to be hydrolyzed reaction, preferably use mineral acid example hydrochloric acid, sulfuric acid or organic acid such as acetic acid to mix and heat and finish with intermediate (III).When using alkali to be hydrolyzed reaction, be with intermediate (III) be placed on alkali metal hydroxide (as, sodium hydroxide, potassium hydroxide) dilute solution in and be heated to that 40 to 100 ℃ (preferably 60-95 ℃) finish.

The description and interpretation that following example is done, to the present invention without any restriction.

Example 1

6.7.8-three fluoro-1-(2-fluoro ethyls)-1,4-dihydro-4-oxygen-3-quinoline carboxylic acid ethyl ester

5.36 6.7.8-three fluoro-1 of kilogram, the mixture of the sodium iodide (being dissolved in 20.5 liters of dimethyl formamides) of 4-dihydro-4-oxygen-3-quinoline carboxylic ester and 2.94 kilograms, under 100 ℃ and condition of stirring, the Anhydrous potassium carbonate that adds 2.97 kilograms, after adding mixture was stirred 15 minutes at 95 to 100 ℃, the toluenesulphonic acids 2-fluorine ethyl ester that then in 2 hours, adds 2.98 kilograms, and mixture heated 1.5 hours between 95-100 ℃, in 2 hours, add 2.73 kilograms toluenesulphonic acids 2-fluorine ethyl ester then again.After heating 4 hours, in 1.5 hours, add 0.82 kilogram tosylate, and under uniform temp, reaction mixture was heated 6 hours.

After the reaction mixture cooling, pour in 64 liters of frozen water, after filtration, the reaction product after the washing puts into 32 liters of methyl alcohol (one-tenth suspended substance) and stirred 30 minutes, filter and drying after (5.02 kilograms in the crystal that obtains, 80.0%) is the purpose product, fusing point 188-190 ℃.

Analyze C ₁₄H ₁₁F ₄NO ₃, calculated value (%), C, 53.00;

H，3.50;N，4.42

Analytical value (%), C, 52.99;

H，3.40;N，4.47

Example 2

6.8-two fluoro-1-(2-fluoro ethyls)-1,4-dihydro-4-oxygen-7-(1-piperazine)-the 3-quinoline carboxylic acid ethyl ester

The 210 gram 6.7.8-three fluoro-1-(2-fluoro ethyls that example 1 is obtained)-1,4-dihydro-4-oxygen-3-quinoline carboxylic acid ethyl ester is added in 50 ℃ of hot solution of 380 gram piperazines (being dissolved in 840 milliliters of methyl-sulphoxides), then temperature of reaction is elevated to 59 ℃, after 30 minutes, add 70 gram carboxylicesterss, under agitation condition, the temperature that keeps reaction mixture is between 55 to 60 ℃, in reaction mixture, add chloroform then, till reaction mixture becomes homogeneous phase, be poured into subsequently in 3.5 liters of frozen water that contain 130 gram salt of wormwood, stir mixture, and tell organic layer, water layer is with chloroform extracting twice, the chloroform of collecting mutually laminated and after, use the saturated common salt water washing, anhydrous sodium sulfate drying, and under reduced pressure be concentrated into crystallization and separate out, last in the reaction mixture 2 liters of hot acetones of adding, the crystal that filtration obtains is expecting compound (242 gram), fusing point 193-195 ℃, filtering-depositing can obtain 32 gram products for the second time, and filtering-depositing can obtain 24 gram products for the third time.

Example 3

6.8-two fluoro-1-(2-fluoro ethyls)-1,4-dihydro-7-(4-methyl isophthalic acid-piperazine)-4-oxygen-3-quinoline carboxylic acid ethyl ester

A, 5.02 kilograms of (15.8 mol) esters that example 1 is obtained join in 15.1 liters of methyl-sulphoxide hot solution (65 ℃) of 3.16 kilograms of (31.6 mol) N methyl piperazines.

The temperature of mixture rose to 85 ℃ automatically in 30 minutes, by heating, in 1.5 hours, keep temperature of reaction between 85 to 90 ℃, the cooling back adds 35 premium on currency diluted mixture things just can obtain product, the product that filtration obtains obtain after with the vinyl acetic monomer recrystallization 5.71 kilograms (90.8%) 6,8-two fluoro-1-(2-fluoro ethyls)-1,4-dihydro-7-(4-methyl isophthalic acid-piperazine)-4-oxygen-3-quinoline carboxylic acid ethyl ester, fusing point 163-165 ℃.

B, 9.5 gram (0.03 mol) esters that example 1 is obtained have joined 6 gram (0.06 mol) N-methyl

In 28.5 milliliters of acetonitrile hot solution of piperazine in (65 ℃), with reaction mixture reflux 5 hours, after the cooling, promptly get crystalline product then with 67 ml water diluted mixture things, with just obtaining purpose product 10.7 grams (89.9%), fusing point 160-163 ℃ behind the vinyl acetic monomer recrystallization.

C, the 9.5 gram esters that example 1 is obtained join in 28.5 milliliters of toluene hot solution (65 ℃) of 6 gram N methyl piperazines, then with reaction mixture reflux 4 hours, behind the concentrating under reduced pressure, promptly get crystalline product with 67 ml water diluted reaction mixtures, with just obtaining purpose product 7.8 grams (65.5%), 159 to 162 ℃ of fusing points behind the vinyl acetic monomer recrystallization.

D, the 9.5 gram esters that example 1 is obtained join in the 38.5 milliliters of spies-butanols hot solution (65 ℃) of 6 gram N methyl piperazines, then with reaction mixture reflux 7 hours, after the cooling, with 67 ml water diluted mixture things, obtain crystalline product, with just obtaining purpose product 10.2 grams (85.7%), 161 to 163 ℃ of fusing points behind the vinyl acetic monomer recrystallization.

E, the 9.5 gram esters that example 1 is obtained join in 28.5 milliliters of dimethyl formamide hot solution (65 ℃) of 6 gram N methyl piperazines, in 30 minutes, the temperature of mixture is raised to 85 ℃ automatically, by heating, in 7 hours, maintain the temperature between 85 to 90 ℃, after the cooling, just can obtain crystalline product with 67 ml water diluted mixture things, behind the vinyl acetic monomer recrystallization, obtain the purpose product (81.5%) of 9.7 grams, fusing point 162-164 ℃.

Analyze C ₁₉H ₂₂F ₃N ₃O ₃, calculated value (%), C, 57.42;

H，5.58;N，10.57

Analytical value (%), C, 57.48;

H，5.49;N，10.56

Example 4

6.8-two fluoro-1-(2-fluoro ethyls)-1,4-dihydro-7-(4-methyl isophthalic acid-piperazine)-4-oxygen-3-quinoline carboxylic acid

A, 5.71 kilograms of esters that example 3 is obtained have joined 1.81 kilograms of sodium hydroxide, in 80 ℃ of hot solution of 61 premium on currency, then reaction mixture is heated to 90 ℃ and kept 20 to 30 minutes, kept again 5 minutes at 90 ℃ then, be adjusted to 6 by adding 4 kilograms of pH values of acetic acid of 68% with reaction mixture, cooling, filtration obtains the crystalline precipitate thing, it is dissolved in the mixture of 68% acetic acid (4.1 liters) and water (33 liters), with 0.4 kilogram of activated carbon treatment, when after the filtration filtrate being heated to 40 ℃, add concentration and be 17.3 kilograms in 35% sulfuric acid, cooling, after the filtration with the sulfate precipitation of collecting, recrystallization in 91 liters water, and then vitriol is dissolved in the solution of 1.57 kilograms of sodium hydroxide and 61 premium on currency, then with 0.4 kilogram of activated carbon treatment solution, filtrate is adjusted to 7.5 ± 0.2 with pH value for about 2.5 liters with 68% acetum, the throw out that filtration obtains joins in 55 liters of ethanol or the methyl alcohol, and stirred 30 minutes, filter, be drying to obtain 269.5 ℃ of 4.48 kilograms of (84.4%) fusing points of purpose product.

Analyze C ₁₇H ₁₈F ₃N ₃O ₃, calculated value (%), C, 55.28;

H，4.91;N，11.38

Analytical value (%), C, 55.42;

H，4.79;N，11.38

B, with 6.8-two fluoro-1-(2-fluoro ethyls)-1,4-dihydro-4-oxygen-7-(1-

Piperazine)-3-quinoline carboxylic acid ethyl ester 297 grams, the mixture of 600 milliliters in formic acid and 39% formalin, refluxed 2 hours, concentrating under reduced pressure then, add 500 ml waters in the resistates of mixture, enriched mixture adds 3 liters of hot water, and is heated to 80 ℃ in resistates once more, under agitation subsequently, handle with containing the 160 gram sodium hydroxide alkalescence aqueous solution, continue stirring and become homogeneous phase until reaction mixture, then restir is 10 minutes, add 3 liters of hot water then, and be heated to 70-80 ℃, with in 80 milliliters of acetic acid and after, collect the washing with alcohol of filtering-depositing with three times of water and 2 times, recrystallization can obtain 6 in methyl-sulphoxide at last, 8-two fluoro-1-(2-fluoro ethyls)-1,4-dihydro-7-(4-methyl isophthalic acid-piperazine)-4-oxygen-3-quinoline carboxylic acid 272 grams, 269 ℃ of fusing points

Analyze C ₁₇H ₁₈F ₃N ₃O ₃, calculated value (%) C, 55.28;

H，4.91;N，11.38

Analytical value (%) C, 55.47;

H，4.82;N，11.36

Example 5

6.8-two fluoro-1-(2-fluoro ethyls)-1,4-dihydro-4-oxygen-7-(1-piperazine) quinoline-3-carboxylic acid

The described method of use-case 4a, the ester that saponification example 2 obtains.

By adding acetic acid the pH value of reaction mixture is adjusted at 7 to 8 o'clock, promptly obtains the purpose compound of a crystal water, 263 ℃ of fusing points (decomposition).

Analyze C ₁₆H ₁₆F ₃N ₃O ₃.H ₂O, calculated value (%), C, 51.48;

H，4.86;N，11.26

Analytical value (%), C, 51.26;

H，4.78;N，11.26

Test 1 anti-microbial activity

The anti-microbial activity of The compounds of this invention is by Gram-positive (G ⁺) and Gram-negative (G ^-) two bacterioids, (Chemo-Therapy therapy, 22,1126 pages, 1974) of examining and determine with the dilution method of scoring of the nutrient agar of standard.

The anti-microbial activity test-results such as the table 1 of The compounds of this invention and known antiseptic-germicide nalidixic acid (NA).The compounds of this invention has higher anti-microbial activity than NA acid to gram-bacteria.

Table 1 anti-microbial activity

(minimum limit concentration, mcg/ml)

Claims (2)

1, the technology of preparation molecule formula IV compound

Here R ₁Be: hydrogen atom or methyl.

This is a molecule formula III compound saponified product.

Here R is: the low molecular weight alkyl of 1 to 3 carbon atom

R ₁Be: hydrogen atom or methyl

This compound is to be made by the reaction of the compound of the compound of molecule formula II and molecule formula I.

The R here ₁With the molecule formula III, the R of (IV) ₁Identical.

Here X is: halogen atom, R is identical with the R of molecule formula III.

2, the preparation molecular formula (technology of compound of IV-a)

This is molecular formula (the compound saponified product of III-b)

Here R is: the low molecular weight alkyl of 1 to 3 carbon atom

This compound is that (compound and the formaldehyde of III-a), the formic acid reaction makes by molecular formula.

(R of III-b) is identical for the R here and molecular formula.