NO761926L - - Google Patents

Description

Process for the production of quinoline-3-carboxylic acids.

The present invention relates to a method for the production of quinoline-3-carboxylic acids and derivatives thereof which have valuable antibacterial properties and can therefore be used as pesticides or as medicines in veterinary and human therapy.

Quinoline-3-carboxylic acids and derivatives thereof represent a very important group of compounds with pharmaceutical applicability. ; l-alkyl-4-oxo-l,4_dihydro-quinoline-3-carboxylic acids are valuable compounds that have antibacterial properties, and one of them, namely 1-ethyl-6 , 7-methylenedioxy -4-oxo-l ,4~dihydroquinoline -3-carboxylic acid (Journal of Medicinal Chemistry 11, l60 (1968) and British Patents Nos. 1,076,828 and 3,287,458,).. have. already been used even in therapy, especially to heal urinary tract infections.

A number of methods are previously known for the preparation of the compounds of this group. According to one variant, dialkyl-anilino-methylene-malonate is ring-closed, resp. derivatives thereof, thereby obtaining alkyl-4-hydroxy-quinoline-3-carboxylates. These compounds are then N-alkylated, the ester group is subjected to hydrolysis, and the 1-alkyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acids obtained are processed into antibacterial preparations.

According to another method, ethyl 2-(anilino-methylene)-acetoacetate is subjected to a ring closure reaction, and then N-alkylation, and the acetyl group of the 3-acetyl-1-alkyl-4-oxo-1,4-dihydroquinoline derivatives formed is converted to a carboxyl group by a so-called "haloform" reaction in the presence of a halogen and an alkali hydroxide solution (Japanese Patent Nos. 72,45-358 and 72,45,359). The reaction appears in form B.

The latter variant has a considerable advantage over the former which consists in the possibility of using the cheaper acetacetic acid ester for the production of ethyl-2-(anilino-methylene)-acetacetate instead of diethylmalonate, which is the starting material for the production of diethyl-anilino-methylene-malonate . On the other hand, there is a serious disadvantage of this reaction with a view to industrial utilization that, due to the poor solubility of 3-acetyl-1-ethyl-4-oxo-1,4-dihydro-quinoline, the reaction can only is conducted in heterophase, and therefore the intended quinoline-3-carboxylic acids are difficult to reproduce and can be obtained in low yields. It has now been shown that the 3-acyl group in 3-acyl-4-oxo-1,4-dihydrop-quinolines can be transferred to a carboxyl group in a two-step process which is easy to carry out also on a large scale. In the first step, an "A" quaternary compound is prepared in the presence of iodine and an aromatic heterocyclic compound containing nitrogen. This reaction is illustrated in Scheme C.

In the present invention, the hydrolysis of the quaternary

connections are protected.

The present invention relates to a process for the production of quinoline-3-carboxylic acids with the general formula:

where R is hydrogen, optionally substituted alkyl.., optionally substituted alkenyl or optionally substituted aralkyl; R1 is hydrogen, halogen, optionally substituted alkyl, optionally substituted, aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted araino, hydroxy, optionally substituted alkoxy, optionally substituted aralkyloxy, optionally substituted acyl, nitro, carboxyl, a derivative of carboxyl or an optionally substituted 5~ to 7-membered heterocyclic ring with 1 - 3 nitrogen atoms which is connected to the quinoline ring over one of the nitrogens,

R 2 is hydrogen, halogen, optionally substituted alkyl, optionally substituted aralkyl, optionally substituted aryl, optionally substituted amino, nitro, hydroxyl, optionally substituted alkoxy, optionally substituted aralkyloxy, or optionally substituted aryloxy;

R 3 is hydrogen, halogen, optionally substituted alkyl, optionally substituted aralkyl, optionally substituted aryl, optionally substituted amino, hydroxyl, optionally substituted alkoxy, or optionally substituted aryloxy; or R 2 and RJ 3 can together with the 5,6-, 6,7- or 7,8-sides of the quinoline ring form an optionally substituted 5- to 7-membered ring optionally containing 1 or 2 heteroatoms which can be oxygen,

. sulfur and/or nitrogen; and .

when n = 0, and R-<3>' is bound to the 8-position of the quinoline ring, R 3 and R together can form an optionally substituted -(CH 2 ) m chain, where m is 2, 3 or 4;

X is oxygen or sulfur;

4

R is hydroxyl or mercapto,

which involves subjecting a compound of the general formula:

where R is hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl or optionally substituted cycloalkyl, R 1 is hydrogen, optionally substituted alkyl, optionally substituted aryl or optionally substituted aralkyl;

Y is an aromatic heterocyclic ring containing a tertiary nitrogen and attached to the ring above the nitrogen or a trialkylamino group; and

Z is an anion,

hydrolysis.

The hydrolysis is preferably carried out in an alkaline medium. As a basic hydrolyzing agent, an alkali hydroxide, e.g. potassium-hydroxy.d , sodium hydroxide; an alkaline earth metal hydroxide, e.g. calcium hydroxide; ammonium hydroxide, or the corresponding carbonates or hydrocarbonates and an alkaline sulphide, e.g. sodium sulfide; an alkaline bisulphide, e.g. sodium bisulphide is used.

Hydrolysis can also be carried out in a neutral or acidic medium,

in the presence of a trialkylamine, preferably triethylamine.

In the presence of the above-mentioned hydrolyzing agents, the hydrolysis is preferably carried out in water or in the presence of water. and a water-miscible organic solvent, e.g. ethanol, acetone, etc.

The temperature during the hydrolysis can vary from 0° to 300°C, but preferably it is between 10° and 200°C.

The mineral acid used for acidifying the reaction mixture is preferably hydrochloric acid, sulfuric acid, or as an organic acid preferably formic acid or acetic acid can be used.

The compound with the general formula I will, during the hydrolysis or after the reaction mixture has been acidified, come together and can be separated by filtration.

The expression "optionally substituted alkyl" preferably denotes an alkyl group, especially methyl, ethyl, n-propyl, i-propyl;

an aminoalkyl group, especially aminomethyl, 1-piperidylmethyl, 2-aminoethyl; a hydroxyalkyl group, preferably hydroxymethyl 1, 1-hydroxyethyl, 2-hydroxyethyl; a haloalkyl group, preferably chloromethyl, 2-chloroethyl; or a cyanoalkyl group, preferably cyanomethyl.

The term "optionally substituted alkenyl" preferably denotes an alkenyl group, preferably allyl, vinyl; an amino-alkenyl group, preferably 3-aminoallyl.

The term "optionally substituted aryl" preferably denotes an aryl group, preferably phenyl, 2-naphthyl, 2-pyridyl, 3-pyridyl, 4-pyridyl; aryl with 1 or 2 substituents, preferably 3,4-dimethylphenyl, 3,4-dimethoxyphenyl.

The term "optionally substituted aralkyl" preferably denotes an aralkyl group, preferably benzyl, 2-phenylethyl; an aralkyl group with 1 or 2 substituents, e.g. (3,4-dimethylphenyl)-methyl, 2-(3,4-dimethoxy-phenyl)-ethyl.

The term "optionally substituted cycloalkyl" preferably denotes a cycloalkyl group, preferably cyclohexyl, cyclopentyl, cycloheptyl, cyclohexylmethyl; a cycloalkyl group with 1 or 2 substituents, preferably 2-hydroxy-cyclohexyl, 3-hydroxy-cyclohexyl, 4-hydroxy-cyclohexyl.

The term "halogen" is preferably chlorine or bromine.

The term "optionally substituted alkoxy" preferably denotes an alkoxy group, and in particular met hoxy, et hoxy, iso-butoxy, n-decyl-oxy, n-octyloxy, n-heptyloxy; an amino- . . . alkoxy group, preferably 2-amino-ethoxy, 2-(1-piperidyl)-ethoxy.

The term "optionally substituted aralkyl" preferably denotes an aralkyl group, more particularly a benzyloxy group;

an aralkyl group with 1 or 2 substituents, preferably 4-methoxy-benzyl, 3,4-dimethoxy-benzyl, 3,4-methylenedioxy-benzyl.

The term "optionally substituted acyl" preferably denotes an acyl group, especially formyl, acetyl, propionyl, benzoyl;

an acyl group with 1 or 2 substituents, preferably hydroxy-acetyl, chloroacetyl, aminoacetyl, (1-piperidyl)-acetyl, 3,4-dimethoxybenzoyl. The "carboxylic acid derivative group" is preferably an alkoxy-carbonyl group, preferably methoxy-carbonyl, ethoxy-carbonyl, benzyloxy-carbonyl; a carboxylic acid amide group, especially carboxamide, N-ethylcarboxamide, piperidylcarbonyl, aziridinylcarbonyl.

The term "optionally substituted 5- to 7-membered heterocyclic group with 1-3 nitrogen atoms" preferably denotes a heterocyclic group, more particularly pyrrolidinyl, piperazinyl, aziridinyl, pyrazolidinyl, imidazolidinyl, indolinyl, pyrrolinyl, -hexahydro-1,3,5-triazinyl , hexahydro-1H-azepinyl; a heterocyclic group with 1 or 2 substituents, preferably 3-hydroxy-pyrrolidinyl, 3-acetoxy-pyrrolidinyl, 3-formyl-pyrrolidinyl, 3-benzyloxy-pyrrolidinyl, 4-methyl-piperazinyl, 4-ethyl-piperazinyl, 4-formyl- piperazinyl, 4-acetyl-piperazinyl, 4-benzyl-piperazinyl.

The groups R 2 and R 3 can together with a 5,6-, 6,7- or 7,8-side of the quinoline ring form a .benzene-, pyridine-, cyclohexene-, cyclopentene-, cycloheptene-, thiazole-, oxazol- , i.sothiazole-, isoxa-zole-, thiazoline-, isothiazoline-, oxazoline-, isoxazoline-, 1,3-dioxole-, 2,3-dihydro-1,4-dioxene- or 2,/f-H-1, 3- dioxene ring, which may optionally be substituted with 1 or more substituents.

As starting materials, the corresponding pyridinium, quinolinium, isoquinolinium, alkyl-substituted pyridinium (preferably, vis picolinium), quinaldinium or lepidinium iodide, bromide,

-perchlorate, -sulphate, -phosphate or -nitrate quaternary salts of the compounds of the general formula II are used. Suitable starting materials are further trialkylammonium iodide, -bromide, -chloride, -perchlorate, -sulfate, -phosphate or -nitrate quaternary salts, of the compounds of the general formula II.

Compounds with the general formula II are new compounds, and can be prepared in the following way:

a) A compound with the general formula:

where n, R, R<1>, R<2>, R<3>, R5, R6 and X are as indicated above, is reacted with a Y-aromatic heterocyclic compound, containing a tertiary nitrogen atom in the presence of iodine, or.

b) a compound with the general formula:

where n, R, R , R , R ,. R , R and X are as above, and Z

denotes a halogen atom, in the presence of a solvent or without a solvent is reacted with a Y-aromatic heterocyclic compound, with a tertiary nitrogen atom, or with. a trialkyl-amino.

In the quaternization reaction, the conventionally used solvents, preferably benzene, acetone, acetohydril, nitromethane, dimethylformamide, etc., can be used.

Further advantages of the present invention will be apparent from the following examples.

Example . 1

2.32 g (5 mmol) of l-ethyl-6,7-methylenedioxy-4-oxo-l,4-dihydro-quinoline-3-ca rbonyl-methyl-pyridinium iodide is sprinkled into a solution of 1 g of sodium hydroxide in 25 ml water, and the reaction mixture is boiled for 1 hour. The mixture is cooled, and the pH is adjusted to 1-2. The precipitated crystals are filtered off, covered with water and dried. 1.1 g (90%) of 1-ethyl-6,7-methylenedioxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid is obtained, which melts at 314°C (decomposition) after recrystallization from dimethylformamide.

Elemental analysis:

Example 2

2.32 g (5 mmol) of 1-ethy1-6,7-methylenedioxy-4~oxo-1,4~dihydro-quinoline-3-carbonyl-methyl-pyridinium iodide are boiled in 25 ml of water in the presence of 28 ml of triethylamine for 16 hours. The solution is then cooled to room temperature and set aside for several days.

The precipitated crystals are filtered off, covered with water and dried. 1.1 g (85%) of 1-ethyl-6,7-methylenedioxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid is obtained, which melts at 313 - 314°C (decomposition) after recrystallization from dimethylformamide . The product from the present example does not cause any melting point reduction when mixed with the product from example 1.

Example 3

2.189 (5 mmol) of 6,7-methylenedioxy-4,oxo-1,4.-dihydro-quinoline-3-carbonyl-methyl-piperidinium iodide is boiled in 25 ml of water in the presence of 1 g of sodium hydroxide for 1 hour. The reaction mixture is cooled to room temperature, and the pH is set to 1 - 2. The precipitated crystals are filtered off. 1.0 g (86%) of 6,7-methylenedioxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid is obtained, which melts above 310°C.

Elemental analysis:

Example 4

2.17 g (5 mmol) of 5,6,8-trimethyl-4-oxo-1,4-dihydro-quinoline-3-carbonyl.1-methyl-pyridinium iodide are boiled in 25 ml of water in the presence of 1 g of sodium hydroxide in 1 hour.. The reaction mixture is cooled to room temperature, and the pH is adjusted to 1 - 2. The precipitated crystals are filtered off, covered with water and dried. 1.10 g. (95%) of 5,6,8-methyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid is obtained, which decomposes at 273 - 275°C.

Elemental analysis:

Example 5

2.31 g (5 mmol) of 1-ethyl-6-chloro-4-oxo-1,4-dihydro-quinoline-3-carbonyl-methyl-pyridinium iodide is boiled in 25 ml of water in the presence of 1 g of sodium hydroxide for 1 hour: The solution cooled to room temperature, and the pH is adjusted to 1 - 2. The precipitated crystals are filtered, covered with water and dried. 1.2 g (96%) of 1-ethyl-6-chloro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid is obtained, which melts at 235 - 237°C.

Elemental analysis:

Example 6

2.25 g (5 mmol) of 1-ethyl-6-methoxy-4-oxo-1,4-dihydro-quinoline-3-carbonyl-raethyl-pyridinium iodide is boiled in 25 ml of water in the presence of 1 g of sodium hydroxide for 1 hour. The solution is cooled to room temperature, and the pH is adjusted to 1 - 2 with an aqueous solution of hydrogen chloride. The precipitated crystals are filtered off, washed with water and dried. 1.07 g (87.0%) of 1-ethyl-6-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid is obtained, which melts at 222 - 223°C.

Elemental analysis:

Example 7

2.16 g (5 mmol) of 1-ethyl-7-methyl-4-oxo-1,4-dihydro-quinoline-3-carbonyl-methyl-pyridinium iodide are boiled in .25 ml of water in the presence of 1 g sodium carbonate for 2 hours. Then set the resolution

ning's pH of 1 - 2 with acetic acid. The precipitated crystals are filtered off, washed with water and dried. 0.95 Q (80%) of 1-ethyl-7-methyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid is obtained, which melts at 285.-2.86°C.

Elemental analysis:

Example 8

2.10 g (5 mmol) of 1-ethyl-4-oxo-1,4-dihydro-quinoline-3-carbonyl-methyl-pyridinium iodide is boiled in 25 ml of water and 5 ml of 34% by weight sodium hydroxide for 1 hour. The reaction mixture cooled to room temperature, and the pH is adjusted to 1 - 2. The precipitated crystals are filtered off, washed with water and dried. 0.90 g (83%) of 1-ethyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid is obtained, which melts at 251 - 252°C.

Elemental analysis:

Example 9

2.039 (5 mmol) of 8-methyl-4-oxo-1,4-dihydro-quinoline-3-carbonyl-methyl-pyridinium iodide is boiled in 25 ml of water, in the presence of 1 g of sodium hydroxide for 1 hour. The solution is cooled to room temperature, and the pH is adjusted to 1 - 2. The precipitated crystals are filtered off, washed with water and dried. 0.90 g (89%) of 8-methyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid is obtained, which decomposes at 276 - 277°C.

Elemental analysis:

Example 10

2.15 g (5 mmol) of 6-nitro-4-oxo-1,4-dihydro-quinoline-3-carbonyl-..methyl-pyridinium iodide are boiled in 25 ml of water in the presence of 1 g of sodium hydroxide for 1 hour. The solution is cooled to room temperature. and the PH is set to .1 - 2. The precipitated crystals are filtered off, washed with water and dried. 1.15 g (98%) of 6-nitro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid is obtained, which melts at 283 - 284°C.

Elemental analysis:

Example 11

1.02 g (2.5 mmol) of 7-hydroxy-4-oxo-1,4-dihydro-quinoline-3-carbonyl-methyl-pyridinium iodide is boiled in 15 ml of water in the presence of

0.5 g sodium hydroxide. The solution is cooled to room temperature. turn, and the pH is adjusted to 1 - 2. The precipitated crystals are filtered off, washed with water and dried. 0.50 g (98%) of 7-hydroxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid is obtained, which melts at 242-244°C.

Elemental analysis:

Claims (7)

1. Procedure for the production of quinoline-3-carboxylic acids with the general formula: • where R is hydrogen, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted aralkyl; R"1" is hydrogen, halogen, optionally substituted alkyl, optionally substituted aryl, ^optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted amino, hydroxy, optionally substituted alkoxy, optionally substituted aralkyloxy, optionally substituted acyl, nitro, carboxylic acid, a carboxylic acid derivative or an optionally substituted 5- to 7-membered heterocyclic ring with 1 3 nitrogens, which is attached to the quinoline ring above the nitrogen; 2 R . is hydrogen, halogen, optionally substituted alkyl, optionally substituted aralkyl, optionally substituted aryl, optionally substituted amino, nitro, hydroxylj optionally substituted alkoxy, optionally substituted aralkyloxy, or optionally substituted aryloxy; R 3 is hydrogen, halogen, optionally substituted alkyl, optionally substituted aralkyl, optionally substituted aryl, optionally substituted amino, hydroxyl, optionally substituted alkoxy or optionally substituted aryloxy, or R 2 and RJ 3 can together with the 5,6-, 6,7- or 7,8-sides of the quinoline ring form an optionally substituted, 5- to 7-membered ring with 1 or 2 heteroatoms which can be oxygen, sulfur or nitrogen ; and 3 when n is 0 and R is bound to the 8-position of the quinoline ring, R3 and R can together form an optionally substituted -(CH2 )m -ring, where m is 2, 3 or 4; X is hydrogen or sulphur, R <4> is hydroxyl or mercapto, characterized in that a compound with the general formula: where n, R, R , R , R and X are as above indicated; ,?:<?. 5 • •}' < ■■ R is hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl or optionally substituted cycloalkyl; R 6 is hydrogen, optionally substituted alkyl, optionally substituted aryl, or optionally substituted aralkyl; Y is an aromatic heterocyclic ring containing a tertiary nitrogen, which is attached above the nitrogen or a trialkylamino group; and Z is an anion, undergo hydrolysis. 2. Method according to claim 1, characterized by . that the hydrolysis is carried out in the presence of hydroxides, carbonates or hydrocarbonates, or organic bases. 3. Process according to claim 1 or 2, characterized in that the hydrolysis is carried out in the presence of ammonium hydroxide, an alkali or alkaline earth metal hydroxide, ammonium carbonate, an alkali or alkaline earth carbonate, an alkali hydrocarbonate or trialkylamine. 4- Method according to claims 1 - 3, characterized in that the hydrolysis is carried out between 0° and 300°C, preferably between 10° and 200°C. 5. Method according to claims 1 - 4, characterized in that the iodide, bromide or chloride salt of a compound of the general formula I is used as starting material for the production of a quinoline-3-carboxylic acid of the general formula I. 6. Method according to claims 1-5, characterized in that a compound of formula II is used where is hydrogen or alkyl, and R^ is hydrogen or alkyl. 7. Process according to claims 1-6, characterized in that 1 -et hy 1-6 , 7-methyleridioxy-4_oxo -1,4-dihydro-quinolin-earbonyl-methyl-1-pyridinium iodide, -chloride or - is used as starting material bromide.