KR900001078B1 - A preparation process for cyclo quinolone derivatives - Google Patents

Abstract

Cycloquinolone derivs. of formula (I) are prepd. by (a) reacting a cpd. of formula (II) with a mixed acid (i.e. 1:10 sodium nitrite/ tetrafluoroboric acid in 1:10 HCl) for 1 hr at 0-5 deg. C to prep. diazonium salt and (b) reacting in org. solvent i.e. dimethylchloride, n-hexane, xylene and water in the presence of mineral salt (i.e. CuCl2, NaF) at 30-150 deg. C or in the absence of mineral salt at 30-200 deg. C. In the formulas, R=H, Me, Et or propyl; Z=halo or substd. amino gp.. (I) are useful as an antibacterial agent.

Description

Method for preparing cycloquinolone derivatives

The present invention relates to a new and advanced method for preparing cycloquinolone derivatives represented by the following general formula (I) and salts thereof, which are powerful antibacterial agents which exhibit a strong bactericidal effect against bacteria.

In general formula (I), R represents hydrogen, methyl, ethyl, propyl, butyl or pentyl group, and Z represents a halogen atom such as chlorine, bromine, pullulose, iodine, monosubstituted amino group, disubstituted amino group, or other hetero A cyclic substituted amino group which may contain atoms, wherein the substituted amino group is hydroxyl, 1 to 6 alkyl atoms, amino, 1 to 6 hydroxy alkyl atoms, 1 to 6 carbon atoms in each alkyl moiety One or more substituents selected from the group consisting of monoalkylamino and dialkyl amino having a group may be further substituted. Cyclic-substituted amino groups refer to 4- to 7-membered cyclic compounds, such as azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, finidyl, amidazolyl, and homo pyrazinyl Included.

Known methods for preparing compounds of Formula (I) include Korean Patent Publication (Publication Nos. 83-7642,84-6989,84-7877,85-4245,85-4962), German Patent No. 3142854, Europe Various manufacturing methods are described in patents 113093, 117473, and the like.

Among the methods described in the above documents, in particular, the preparation method described in German or European Patent or Korean Patent Publication (Publication No. 83-7642,84-6989,84-6990) is described as 3-Pluor-4,6-dichlorobenzoic acid. This starting material is not easy to purchase or acquire, and even if it is manufactured by itself, it can be obtained through 2 or more steps from 2,4-dichloro-5-methylaniline. Because acid must be used, it has the disadvantage of requiring special equipment and design and is not suitable for industrial mass production. Other patents also have drawbacks that the process is too long and yields are extremely low.

However, the present invention, unlike the known methods described above, does not require a difficult reaction process and is an economical and progressive method. It azoizes a compound of formula (II), which is a novel starting material of the present invention, and halogenates it. It is a method of manufacturing the cycloquinolone derivative of (I). Of course, it can be obtained by hydrolysis even when R in the general formula (I) is hydrogen.

The compound of the general formula (I) of the present invention can generate acid addition salts with inorganic acids such as hydrochloric acid and sulfuric acid, or organic acids such as methanesulfonic acid, and can also produce sodium, potassium and the like and the corresponding carboxylic acid salts.

Z and R in general formula (II) are the same as general formula (I).

In more detail, the diazonium salt is produced by reacting the compound of formula (II) with mixed acid in dilute hydrochloric acid (hydrochloric acid 1: distilled water 10) at 0 ° C. to 5 ° C. within 1 hour. This diazonium salt was dissolved in a solvent such as dimethyl chloride, n-hexane, n-heptane, benzene, toluene, xylene, water, mineral oil, Dowsome A, paraffin oil, CuCl ₂ , nickel chloride Reaction is carried out at 30 ° C. to 150 ° C. in the presence of an inorganic salt such as cobalt chloride (CoCl ₂ ), sodium fluoride, or potassium fluoride, or heated at 30 ° C. to 200 ° C. in the absence of an inorganic salt of general formula (I). To prepare cycloquinolone derivatives. Mixed acid is a mixture of sodium nitrite and tetrafluoroboric acid, sodium nitrite and hexafluorophosphoric acid, and the composition ratio is preferably 1:10. When R is hydrogen in the produced compound of general formula (I), it can be easily prepared by heating at 60 ° C.-100 ° C. alone or in the presence of a mixed aqueous solution such as sodium hydroxide and potassium hydroxide.

The diazonium salt compound is heated with copper chloride at 80 ° C. to 150 ° C. in a mineral oil solvent to give a high yield of cycloquinolone derivative of general formula (I). At this time, the equivalent ratio of copper chloride and general formula (II) is preferably 0.5 to 1.0, and the equivalent ratio of sodium nitrite and general formula (II) is preferably 1.2 to 1.5. When Z is an amino group in a derivative of a monoamine group or a cyclic-substituted amino group in formula (II), the amino group is protected with an appropriate acetyl compound and the halogenation reaction is carried out.

The theoretical invention from which compounds of formula (I) can be obtained from compounds of formula (II) is described in J. Med. Chem. 27, 292 (1984), J. Am. Chem. Soc., 78, 6037 (1956), J. Org. Chem., 28, 568 (1963). However, in the present invention, the compound of formula (II) may be prepared from the general formula (VIII), which is a known compound, as a novel compound through the following process. Hel. Chim. Acta. 40, 1187 (1957).

In each of the above general formulae, R and Z are as defined in general formula (I). In other words, the reaction process for preparing the compound of formula (II) from the carboxylic acid of formula (VIII) is described, the thionyl chloride and the compound of formula (VIII) is heated at 80 ℃ to 100 ℃, fractionation Distillation under reduced pressure gives chlorobenzoic acid of the general formula (VII). The compound of formula (VII) is heated with diethyl malonate at 50 ° C. to 100 ° C. in the presence of a mixed organic solvent of metal ions such as sodium, magnesium or potassium, carbon tetrachloride, ethanol and ether to obtain a compound of formula (VI). . Next, the mixture is heated at a temperature of 50 ° C. to 150 ° C. while stirring in an organic polar solvent such as dimethyl sulfoxide, dioxane, dimethylformamide, pyridine and the like to obtain a compound of formula (IV).

The compound of formula (IV) and methyl ortho formate or ethyl ortho formate were heated and stirred for 2 to 4 hours at 120 ° C. to 160 ° C. in an acetic anhydride solvent, followed by distillation under reduced pressure, and sodium hydride was added to the remaining residue. The compound of formula (III) is obtained by heating and stirring at 50 ° to 150 ° C. under an organic solvent such as amide or dioxane. The nitro group of the general formula (III) compound is reduced to 2 to 3 atmospheres of hydrogen gas in the general reduction using sodium orionate or iron-hydrochloric acid, or in the presence of organic solvents such as palladium carbon, raninickel, formic acid, methanol and ethanol. Catalytic reduction produces new compounds of formula (II). The preparation of compounds such as piperazinyl, piperidinyl, morpholine, etc., in which the substituents in the compound of formula (II) may be carried out using compounds of general formula (IV) or general formula (III), such as piperazine, piperidine, morpholidine And a compound such as dimethyl sulfoxide, pyridine, dimethylformamide, and the like, and heated to 100 ° C to 250 ° C.

Thus, the compound of the general formula (II) which is the starting material of the present invention can be prepared by the method described above using a cheap and easy to obtain the general formula (VIII) compound as a starting material. The process of the present invention is therefore a new and advanced process when compared to conventional methods which require the use of certain specific starting materials or special equipment for the manufacture or which require too long a process.

The reaction is usually completed in 1 to 10 hours and the product can be separated and purified by conventional techniques such as evaporation, filtration, extraction, chromatography, recrystallization and combinations thereof. For example, when the product precipitates by cooling the reaction mixture, the precipitate is collected by filtration. If no precipitation occurs, the reaction mixture is concentrated under reduced pressure to dryness and the residue is diluted with dimethylchloride, chloroform or ethyl. The product is obtained by shaking with a mixture of water and an organic solvent such as acetate and then concentrating the organic solvent. If the product contains by-products, it can be further purified by chromatography or recrystallization.

The present invention will be described in more detail with reference to the following examples, but the present invention is not necessarily limited to this range. Unless otherwise indicated, percentages, percentages, etc., are by weight.

Example 1

2,4-dichloro-5-nitro benzoic acid (VIII)

300 g (1.57 mol) of dichlorobenzoic acid are added to 800 ml of 90% sulfuric acid, cooled, and slowly added 100 ml of 71% nitric acid and 700 ml of 96% H ₂ SO ₄ at 0 ° C. After stirring for 3 hours at room temperature, the reaction solution was diluted with 1 l of water, filtered, and washed three times with water. At 50 ℃ reduced pressure (30mmH _g) dried to give an off-white solid 304g (82%).

m.p. : 153-156 ℃

nmr (DMSO-d6) ppm: 8.17 (S, 1H), 8.57 (S, 1H)

IR (KBr) cm ^-1 : 3036 (m), 1715 (S), 1595 (S), 1550 (S), 1525 (m), 1298 (m), 1256 (S)

Example 2

2,4-dichloro-5-nitrobenzoyl chloride (VII)

100 g (0.42 mole) of 2,4-dichloro-5-nitrobenzoyl acid are mixed with 176 g (1.48 mole) of thionyl chloride, and then heated and stirred for 3 hours. The remaining excess thionyl chloride was distilled off and then distilled at 154 ° C.-159 ° C. under 2-4 mmH _g reduced pressure to give a pale yellow liquid product.

Example 3

Ethyl 2,4-dichloro-5-nitrobenzoyl acetate (VI)

Magnesium (10.3 g) and diethyl malonate (7.8 ml) are added to a mixed solution of 21 ml of ethanol and 2 ml of carbon tetrachloride and stirred by heating. To this solution is slowly added ethylmalonate (60 ml) dissolved in 40 ml of ethanol and 170 ml of ether. The reaction mixture is heated until magnesium is used up, and then the solution is cooled to -10 ° C using dry ice. Here, 2,4-dichloro-5-nitrobenzoyl chloride prepared in Example 2 is dissolved in 100 ml of methylene chloride and slowly added thereto. The reaction is stirred at room temperature for 2 hours. The neutralized solution was extracted with methylene chloride and dried, and then the solvent was removed to obtain 141.5 g (88%) of diethyl (2,4-dichloro-5-nitro) benzoyl malonate.

NMR [(CDCl ₃ ) ppm: 0.9-1.5 (m, 6H), 3.31 (S, 1H), 4.0-4.5 (m, 4H), 5.30 (S, 1H), 7.70 (S, 1H), 8.03 (S , 1H) M.

The above product was put in 1 g of paratoluene sulfonic acid and 200 ml of water, heated for 4 hours, extracted with dimethylene chloride, and the organic solvent was dried and then distilled at low temperature. The residue was recrystallized from a mixed solution of petroleum ether and hexane [5: 1 (v / v)] to give 108.4 g (95%) of a pale yellow solid.

m.p. : 67-68 ℃

nmr (CDCl ₃ ) ppm: 1.23-1.39 (m, 3H), 4.05 (S, 1H), 4.15-4.35 (m, 2H), 5.68 (S, 1H), 7.68 (S, 1H), 8.24 (S, 1H).

IR (KBr) cm ^-1 : 1706 (m), 1642 (S), 1550 (S), 1530 (S), 1475 (S), 1415 (S), 1385 (S), 1340 (S), 1250 ( S), 1200 (S).

Example 4

Ethyl 2-cyclopropylamino-4-chloro-5-nitrobenzoyl acetate (IV) (Z = Cl)

The above product (VI) (30.6 g, 0.1 mole) and cyclopropylamine (26.5 g, 0.5 mole) are added to an organic solvent of 100 ml of dimethyl sulfoxide and 20 ml of pyridine and stirred at 150 ° C. for 2 hours. The solution is blown off under reduced pressure distillation, dimethylene chloride is added, the organic solvent is washed with 1N HCl, saturated bicarbonate water, water, saturated brine, and dried. The organic solvent was removed and the residue was purified by silica gel chromatography to give a light yellow solid, product, 26.2 g (81%).

m.p: 72-76 ° C

nmr (CDCl ₃ ) ppm: 0.81-1.20 (m, 7H), 3.30-3.62 (m, 1H), 4.21 (m, 2H), 5.42 (S, 1H), 7.12 (S, 1H), 7.81 (S, 1H).

IR: 3180 (W), 1700 (m), 1650 (S), 1540 (S), 1410 (S), 1340 (S), 1200 (S) M.

Example 5

Ethyl 1-cyclopropyl-6-nitro-7-chloro-1,4-dihydro-4-oxoquinoline-3-carboxylate (III) (Z = Cl)

16.2 g (0.05 mol) of the above product (IV) was added to 12.5 ml (0.073 mol) of ethyl orthoformate and 12 ml of acetic anhydride and stirred at 80 ° C. for 3 hours. The solvent was blown under reduced pressure and dried to give 20.6 g (98%) of ethyl 1-cyclopropyl-4-chloro-5-nitrobenzoyl-3-ethoxy acrylate. The product was slowly added to 100 ml of dioxane and 1.8 g of 80% sodium hydride at 0 ° C., stirred at room temperature for 1 hour, and then stirred by heating for 3 hours. The dioxane solution is washed and dried in the order of 1N hydrochloric acid, saturated bicarbonate water, water and brine. After blowing off the organic solvent, the residue was recrystallized in ethanol solution to give 13.8 g (82%) of a yellow solid.

m.p: 242 ℃ -245 ℃

nmr (CF ₃ COOD) ppm: 1.50-1.83 (m, 7H), 4.0-4.33 (m, 1H), 4.35-4.90 (q, 2H), 7.85 (S, 1H), 8.17 (S, 1H), 8.50 (S, 1 H).

IR (KBr) cm ^-1 : 1730 (S), 1630 (S), 1595 (S), 1325 (S)

Example 6

Ethyl 1-cyclopropyl-6-amino-7-chloro-1, 4-dihydro-4-oxoquinoline-3-carboxylate (II) (Z = Cl)

3.7 g (0.01 mol) of the above product (III) was added to 50 ml of methanol, 0.5 g of palladium carbon was added, and reacted for 5 hours under hydrogen gas at 3 atmospheres. After filtering the reaction, the solution was distilled under reduced pressure to yield 3.0 g (98%) of the amine compound (II).

IR (KBr) cm ^-1 : 3445 (W), 3327 (m), 1710 (S), 1610 (S), 1580 (S), 1495 (S), 1320 (S), 1255 (S)

Example 7

1-cyclopropyl-6-Pluoro-7-chloro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (I) (Z = Cl)

3.0 g (0.01 mol) of the above product (II) was added to 30 ml of 1N hydrochloric acid, and slowly added to 10 ml of an aqueous solution containing 1 g (0.015 mol) of sodium nitrite while maintaining the temperature at 0 ° C. Into the reaction solution, 60% 6 pullourophosphate is added to precipitate. The precipitate is filtered off and dried under reduced pressure. This product is poured into 30 ml of mineral oil and stirred with 1 g of copper chloride at 120 ° C. for 30 minutes. The precipitate is filtered off and washed three times with dimethylene chloride. The filtrate was added to 15 ml of water, KOH (1.0 g) was added, and the mixture was heated and stirred. The precipitate is acidified, filtered and washed with water. Recrystallization from dimethyl formamide gave 2.0 g (71%) of a white solid.

m.p. 230-235 ℃

nmr (DMSO-d6) ppm: 0.75-0.91 (m, 4H), 3.32-3.60 (m, 1H), 7.42-7.45 (d, J = 5.5H, 1H), 7.89-7.94 (d, J = 9H, 1H), 8.25 (S, 1H).

Example 8

1-cyclopropyl-6-Pluoro-7-piperazinyl-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (I) (Z = piperazinyl)

Obtained using a method similar to that described in Example 7 above. Recrystallized from using dimethylformamide as a solvent.

m.p: 250-255 ℃

nmr (CF ₃ COOD) ppm: 0.40-0.69 (m, 4H), 2.45-2.80 (m, 8H), 2.91-3.02 (m, 1H), 6.88-6.91 (d, J = 5H, 1H), 7.25- 7.29 (d, J = 9H, 1 H), 7.60 (S, 1 H).

Example 9

1-cyclopropyl-6-nitro-7-piperazinyl-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid Similar to the method described in the above example, an orange solid was obtained.

m.p: 290-300 ℃

nmr (CF ₃ COOD) ppm: 0.48-0.76 (m, 4H), 2.80-3.10 (m, 8H), 3.13-3.16 (m, 1H), 7.12 (S, 1H), 8.18 (S, 1H), 8.45 (S, 1 H).

Example 10

1-cyclopropyl-6-nitro-7-chloro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid

Similar to the method described in the above example, recrystallization from acetonitrile gave a yellow solid.

m.p. : 268-270 ℃

nmr (DMSO-d6) ppm: 1.22-1.38 (m, 4H), 3.88 (m, 1H), 8.52 (S, 1H), 8.78 (S, 1H), 8.87 (S, 1H).

Claims (9)

A compound of formula (II) is reacted with mixed acid at 0-5 ° C. to produce diazonium as an intermediate, and the resulting diazonium is reacted in the presence of an organic solvent and an inorganic salt or in the absence of an inorganic salt. Method for producing a cycloquinolone derivative of (I).

R in formulas (I) and (II) represents a hydrogen, methyl, ethyl, propyl, butyl or pentyl group, and Z represents a chlorine, bromine or piperazinyl group. The method for preparing a cycloquinolone derivative of formula (I) according to claim 1, wherein the mixed acid consists of a mixture of sodium nitrite and tetrafluoroboric acid or sodium nitrite and hexafluorophosphoric acid. The organic solvent of claim 1, wherein the organic solvent is selected from dimethyl chloride, n-hexane, n-heptane, benzene, toluene, xylene, water, mineral oil, Dowsome A, or paraffin oil, alone or in a mixture. Process for the preparation of cycloquinolone derivatives of general formula (I). The method for producing a cycloquinolone derivative of formula (I) according to claim 1, wherein the inorganic salt is prepared by selecting from nickel chloride, copper chloride, cobalt chloride, sodium fluoride or potassium fluoride. The method for preparing a cycloquinolone derivative of formula (I) according to claim 1, wherein the reaction temperature is 30 ° C to 150 ° C in the presence of an inorganic salt. The method for preparing a cycloquinolone derivative of formula (I) according to claim 1, wherein the reaction temperature is 30 ° C to 200 ° C in the presence of an inorganic salt ratio. A compound of Formula (II) comprising a first step of cyclizing a diketone compound of Formula (IV) to produce a compound of Formula (III) and a second step of aminating an compound of Formula (III). Manufacturing method.

In each of the above general formulae, R represents hydrogen, methyl, ethyl, propyl, butyl or pentyl group, and Z represents chlorine, bromine or piperazinyl group. 8. The process of claim 7, wherein in the cyclization of the first step, methylorthoformate or ethylorthoformate is first reacted at 120-160 ° C. in acetic anhydride and secondly sodium hydride is dissolved in dimethylformamide or dioxane solvent. A process for preparing a compound of formula (II), characterized in that it reacts at -150 ° C. 8. The general formula (II) according to claim 7, wherein in the amination of the second step, the reducing agent of sodium ionic acid, iron and hydrochloric acid, palladium carbon or Raney nickel is reduced to hydrogen gas in the presence of a formic acid, methanol or ethanol solvent. ) Method of preparing the compound.