The way to obtain 1-ethyl-6-fluoro-7-(piperazinil-1)-4-oxo-1,4 - dihydro-3-quinoline-carboxylic acid

 

(57) Abstract:

Usage: as an antibiotic of the fourth generation. The essence of the invention: a method of obtaining a 1-ethyl-6-fluoro-7-(piperazinil-1)-4-oxo-1, 4-dihydro-3-quinoline-carboxylic acid f-crystals 1 interaction 1-ethyl-6-fluoro-7-halogeno-4-oxo-1, 4-dihydro-3-quinoline-carboxylic acids or their esters with uranyl piperazine in the presence of potassium carbonate or triethylamine in aqueous solution. Connection structure of f-crystals 1

< / BR>
table 1.

The invention relates to organic chemistry, and in particular to methods obtain 1-ethyl-6-fluoro-7-(piperazinil-1)-4-oxo-1,4-dihydro-3-quinoline-carboxylic acid (norfloxacin) formula 1

which is a synthetic antibiotic with a broad spectrum of antibacterial activity, is among the five most active fluoroquinolones (ciprofloxacin, pefloxacin, norfloxacin, enoxacin, ofloxacin) and used as an antibiotic of the fourth generation.

The majority described in patent literature methods of obtaining norfloxacin is the reaction of substitution of the chlorine atom in derivatives of 6-fluoro-7-chloro-4-oxo-1,4-dihydro-3-quinoline-carboxylic acid under distearate [4] where the key intermediate product is 1-ethyl - 6-fluoro-7-chloro-4-oxo-1,4-dihydro-3-Hino - linkarena acid (II), and the substitution of the chlorine atom is under the influence of more affordable uranyl piperazine.

____< / BR>
The substitution reaction of the chlorine atom in the acid II for the remainder of the piperazine is carried out in water or in the absence of solvent at 135-170aboutWith the autoclave for 16-18 hours Output norfloxacin is 54%

The main disadvantage of these methods of synthesis norfloksatsina is the low mobility of the chlorine atom in position 7, which does not allow to achieve high yields of final product at the stage of replacement of chlorine in 1-ethyl-6-fluoro-7-chloro - 4-oxo-1,4-dihydro-3-quinoline-carboxylic acid for the remainder of the piperazine. Due to the low mobility of the chlorine atom in position 7 in the conditions of the synthesis side flows the process of substitution of fluorine at position 6, which leads to the formation of similar norfloksatsina not possessing antibacterial activity, which contaminates the target product and makes it difficult isolation and purification [5]

The aim of the invention is to increase the selectivity of the process and output of the target product, as well as simplification of the process.

This goal is achieved by the fact that as the source of 6,7-dehalogenating 3-quinoline-carboxylic acid using 1-ethyl-6,7-debtor-4-oxo - 1, 7 compared with chlorine analogues significantly simplify technology for norfloksatsina and increase its output.

The reaction is carried out by boiling a mixture of 1-ethyl-6,7-debtor-4-oxo-1,4-dihydro-3-Hino - incarbone acid, uranyl piperazine and triethylamine or potassium carbonate in aqueous solution for 5 hours is Optimal ratio of 6.7-littorinimorpha acid III piperazine, the uranyl an triethylamine (potassium carbonate) 1:3:2.5 mol. Reducing the number of piperazine and triethylamine or potassium carbonate reduces the yield of the target product. The resulting reaction target product norfloxacin (I) distinguish the known methods. The output norfloxacin after recrystallization from ethanol, isopropanol or 50% aqueous dimethylformamide is 78-80%

Norfloxacin may also be obtained by boiling a mixture of ethyl ester 1-ethyl-6,7-debtor-4-oxo-1,4-dihydro-3-Hino - incarbone acid (IV), piperazine uranyl and triethylamine in aqueous solution for 10 hours reducing the time of reaction leads to lower output norfloxacin. The optimal ratio of reagents ether hinolincarbonova acid IV triethylamine, the uranyl piperazine 1:2,5:3 mol. Conducting the reaction in water leads to the fact that along with the substitution of the fluorine atom in the piperazine hydrolysis ether IV to sour the quinoline - carboxylic acid is 67-70% of the Structure of 1-ethyl-6-fluoro-7-(piperazinil-1)-4-oxo-1,4-dihydro-3-quinoline-carboxylic acid 1 confirmed by the data of elemental analysis, IR, NMR1H and19F spectroscopy, mass spectrometry.

Comparative characteristics of the proposed method with the prototype is given in the table.

Carrying out the reaction of 1-ethyl-6-fluoro-7-chloro-4-oxo-1,4-dihydro-3-hinolinova new acid and its ethyl ester with uranyl piperazine in conditions similar to the proposed invention, has not led to the synthesis of norfloxacin, were allocated to the original products.

Thus, using as a key intermediate 1-ethyl-6,7-debtor-4-oxo-1,4-dihydro-3-hinolinova new acid and its ethyl ester in the synthesis of norfloxacin significantly simplify technology (instead of anhydrous hydrazine is used more than available, the uranyl, the reaction is carried out in aqueous solution by boiling) and to increase the yield of the target product.

P R I m e R 1. In a two-neck round bottom flask with a capacity of 250 ml, equipped with a bubbler, placed 120 ml of water, to 25.3 g (0.1 mol) of 1-ethyl-6,7-debtor-4-oxo-1,4-dihydro-3-quinoline-carboxylic acid, 58,3 g (0.3 mol) of piperazine uranyl and 34.6 ml (25,3 g, 0.25 mol) of triethylamine and refluxed in a stream of inert gas for 5 hours After cooling the reaction solution in the flask p. and dried. After recrystallization from ethanol or 50% aqueous dimethylformamide gain of 25.2 g (79%) of 1-ethyl-6-fluoro-7-(piperazinil-1)-4-oxo-1,4-dihydro-3-fineliner - oil acid (norfloxacin).

Found, With 60,0; H 5,7; N 13,1.

WITH16H18FN3O3< / BR>
Calculated With A 60.2; H 5,7; N 13,0.

So pl. 227-228aboutC.

An NMR spectrum1N (CF3COOD) of 1.78 (3H, t, JN-N-7 Hz, CH3); 3.7 to 4.1 (8H, m, CH2piperazine); 4,88 (2H, q, JN-N=7 Hz, CH2); to 7.50 (1H, d, JN-F=6,5 Hz, 8-H); 8,35 (1H, d, JH-F=12,5 Hz, 5-H); TO 9.32 (1H, s, 2-H) M. D. NMR19F: 41,2 M. D. (1F, kV, 6-F). IR spectrum (KBR) 1620 (C=O). Mass spectrum 319 (M+), 277, 275, 233.

P R I m m e R 2. In a two-neck round bottom flask with a capacity of 250 ml, equipped with a bubbler, placed 120 ml of water, to 25.3 g (0.1 mol) of 1-ethyl-6,7-debtor-4-oxo-1,4-dihydro-3-hee - noonkanbah acid, 58,3 g (0.3 mol) of uranyl piperazine and of 34.5 g (0.25 mol) of potassium carbonate and heated in a current of inert gas from the reverse water refrigerator 5 hours After cooling the reaction mass with stirring, add 20-25 ml of acetic acid to a pH of 7.5-8.5. The precipitation in 15-20 min filtered off and recrystallized from ethanol or 50% aqueous dimethylformamide. After drying at 110aboutWith those who P>aboutC. the Structure is confirmed by NMR1H and19F spectroscopy.

P R I m e R 3. In a round bottom flask with a capacity of 250 ml is placed 120 ml of water, to 25.3 g (0.1 mol) of 1-ethyl-6,7-debtor-4-oxo-1,4-dihydro-3-quinoline-carboxylic acid, of 19.4 g (0.1 mol) of uranyl piperazine and 10.1 g (of 13.8 ml, 0.1 mol) of triethylamine and heated in a current of inert gas under reflux 5 hours Acidified with acetic acid to a pH of 7.5-8.5 and after 15-20 minutes the precipitation is filtered off. After recrystallization from ethanol and drying at 110aboutC for 4 h are of 17.2 g (54%) of 1-ethyl-6-fluoro-7-(piperazinil-1)-4-oxo-1,4-dihydro-3-quinoline-carboxylic acid. Not dissolved in ethanol precipitate is recrystallized from dimethylformamide and obtain 6.3 g (25%) of unreacted 1-ethyl-6,7-debtor-4-oxo-1,4-dihydro-3-quinoline-carboxylic acid. Its structure is confirmed by elemental analysis and NMR1H and19F spectra.

P R I m e R 4. In a two-neck round bottom flask with a capacity of 250 ml was placed 150 ml of water, and 28.3 g (0.1 mol) of ethyl ester 1-ethyl-6,7-debtor-4-oxo-1,4-dihydro-3-Hino - incarbone acid, 58,3 g (0.3 mol) of uranyl piperazine and 34.6 ml of 25.2 g, 0.25 mol) of triethylamine and boil with the reverse water refrigerator in a stream of inert gas 10 o'clock P is filtrowa and after recrystallization from ethanol or aqueous 50% of dimethylformamide and drying at 110aboutWith in 4 hours to obtain 22 g (69% ) of 1-ethyl-6-fluoro-7-(piperazinil)-4-oxo-1,4-dihydro-3-quinoline-carboxylic acid. The structure is confirmed by NMR1H and19F spectroscopy.

P R I m e R 5. In a round bottom flask with a capacity of 250 ml was placed 150 ml of water, and 28.3 g (0.1 mol) of ethyl ester 1-ethyl-6,7-debtor-4-oxo-1,4-dihydro-3-fineliner - oil acid, 58,3 g (0.3 mol) of uranyl piperazine and 34.6 ml of 25.2 g, 0.25 mol) of triethylamine and boil with the reverse water refrigerator in a stream of inert gas 5 hours After cooling, acidified with acetic acid to a pH of 7.5-8.5, the precipitation is filtered off. After recrystallization from ethanol and drying at 110aboutWith in 4 hours to obtain 16.3 g (51% ) of 1-ethyl-6-fluoro-7-(piperazinil-1)-4-oxo-1,4-dihydro - 3-quinoline-carboxylic acid, its structure is confirmed by elemental analysis and NMR1H and19F spectra.

P R I m e R 6. In a two-neck round bottom flask with a capacity of 150 ml was placed 120 ml of water, and 26.9 g (0.1 mol) of 1-ethyl-6-fluoro-7-chloro-4-oxo-1,4-dihydro-3-quinoline-carboxylic acid, 58,3 g (0.3 mol) of uranyl piperazine and 34.6 ml (25,3 g, 0.25 mol) of triethylamine and refluxed in a stream of inert gas 5 hours After cooling, acidified with acetic acid to a pH of 7.5-8.5 and hoteltravel is divided by the original 1-ethyl-6-fluoro-7-chloro-4-oxo-1,4-dihydro-3-quinoline-carboxylic acid.

P R I m e R 7. In a two-neck round bottom flask with a capacity of 250 ml is placed to 29.8 g (0.1 mol) of ethyl ester 1-ethyl-6-fluoro-7-chloro-4-oxo-1,4-dihydro-3-quinoline-carboxylic acid, 150 ml of water, 58,3 g (0.3 mol) of uranyl piperazine and 34.6 ml (25,3 g, 0.25 mol) of triethylamine and heated in a current of inert gas 10 o'clock After cooling the acidified reaction mass of acetic acid to a pH of 7.5-8.5 and the precipitation is filtered off. According to TLC, NMR1H and19F, with a yield of 78% is obtained 1-ethyl-6-fluoro-7-chloro-4-oxo-1,4-dihydro-3-quinoline - carboxylic acid.

The WAY to OBTAIN 1-ETHYL-6-FLUORO-7-(PIPERAZINIL-1)-4-OXO-1,4-DIHYDRO-3-quinoline-carboxylic ACID formula

< / BR>
the reaction of 1-ethyl-6-fluoro-7-halogeno-4-oxo-1,4-dihydro-3-quinoline-carboxylic acids with uranyl piperazine, characterized in that, to increase the yield of the target product and simplifying the technology of the process, as a source of 6,7-dehalogenating 3-quinoline-carboxylic acid using 1-ethyl-6,7-debtor-4-oxo-1,4-dihydro-3-quinoline-carboxylic acid or its ethyl ester.

 

Same patents:

The invention relates to new indole derivative of General formula

I where R1hydrogen or C1-4-alkyl;

R2hydrogen or C1-4-alkyl;

R3hydrogen or C1-3-alkyl,

or their pharmaceutically acceptable salt, or solvate having NC1-like receptor antagonistic activity

The invention relates to new derivatives of azetidine General formula:

O-R7 (I) where a nitrogen atom or the group-CH-, or C-HaI, where HaI, a chlorine atom or fluorine;

R1lower alkyl or cycloalkyl, lower halogenated or phenyl substituted mono - or Diptera;

R2, R3and R5the same or different and signify hydrogen or lower alkyl;

R4hydroxyl, amino, aminoalkyl, alkylamino, dialkylamino, pyrrolyl-1 or pyrrolidinyl-1, acylaminoalkyl, trifurcated;

R6hydrogen or amino group,

or

A and R1together form a group-O-CH2-and in this case have a chiral center configuration R or S,

R7hydrogen or lower alkyl,

or their pharmaceutically acceptable salts

The invention relates to new derivatives of intellipedia General formula

where R1phenyl substituted by substituents selected from the group consisting of lower alkyl, hydroxyl, protected hydroxyl, halogen or lower alkoxy,

And lower alkylen,

In the lower albaniles, or their pharmaceutically acceptable salts which exhibit anti-allergic effect

The invention relates to new biologically active pyridyl - or pyrimidinediamine derivative of piperazine or 1,4-disallocation, or their pharmacologically active acid additive salts with psychotropic action

The invention relates to new derivatives of benzimidazole, method of production thereof and their use as medicines

FIELD: chemistry.

SUBSTANCE: invention relates to derivatives with anticancer activity of formulae:

, , , , ,

R2', R3', R4', R5' and R6' are selected from H, Y(CH2)nCH3, X and (CH2)nNR8R9; Y is selected from O and S; X is selected from F, Cl and Br; R8 and R9 are selected from (CH2)nCH3; R2, R3, R4 and R5 are selected from H, Y(CH2)nCH3, X and (CH2)nNR8R9, or R3 and R4 together form -Y(CH2)nY-; R1 and R1' are selected from H, Li+, Na+, K+, N+R8R9R10R11 or benzyl, where R10 and R11 are selected from H, (CH2)nYH, (CH2)nN(CnH2n+1)(CmH2m+1) or (CH2)nCH3, where n and m are integers from 0 to 4, q is an integer from 1 to 4.

EFFECT: obtaining novel compounds with anticancer activity.

37 cl, 3 dwg, 10 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new quinolone derivatives of general formula (1) or a pharmaceutically acceptable salts thereof, wherein R1 represents a hydrogen atom, a lower alkyl group, cyclo C3-8 alkyl, a lower alkyl group or a lower alkoxy, a lower alkyl group; R2 represents a hydrogen, a lower alkyl group or a halogen-substituted lower alkyl group; R3 represents a phenyl group, a difurylglyoxal group, a thienyl group or pyridyl group with each group of the above is optionally substituted by one or two groups specified in a group consisting of the following (1) to (16) in an aromatic or heterocyclic ring, presented by the above R3: (1) lower alkyl groups, (2) lower alkoxy groups, (3) halogen-substituted lower alkoxy groups; (4) a phenoxy group, (5) lower alkylthio groups, (6) a hydroxy group, (7) hydroxy lower alkyl groups, (8) halogen atoms, (9) lower alkanoyl groups, (10) lower alkoxycarbonyl groups, (11) amino groups optionally substituted by one or two lower alkyl groups, (12) carbamoyl groups optionally substituted by one or two lower alkyl groups, (13) cyclo C3-8 alkyl lower alkoxy groups, (14) pyrrolidinyl carbonyl groups, (15) morpholinyl carbonyl groups and (16) a carboxyl group; R1 represents a halogen atom; R5 represents a hydrogen atom or a halogen atom; R6 represents a hydrogen atom; and R7 represents any of the above groups (1) to (15): (1) a hydroxyl group, (2) a halogen atom, (3) a lower alkoxy group, (4) a halogen-substituted lower alkoxy group, (5) a hydroxy lower alkoxy group, (6) a lower alkoxy lower alkoxy group, (7) an amino group optionally substituted by one or two members specified in a group consisting of lower alkyl groups, lower alkoxy lower alkyl groups and cyclo C3-8 alkyl groups, (8) an amino lower alkoxy group optionally substituted in an amino group by one or two members specified in a group consisting of lower alkyl groups, lower alkanoyl group, lower alkyl sulphonyl groups and carbamoyl groups optionally substituted by one or two lower alkyl groups, (9) a cyclo C3-8 alkoxy group, (10) a cyclo C3-8 alkyl lower alkoxy group, (11) a tetrahydrofuryl lower alkoxy group, (12) a lower alkylthio group, (13) a heterocyclic group specified in a group consisting of morpholinyl groups, pyrrolidinyl groups, difurylglyoxal groups, thienyl groups and benzothienyl groups, (14) a phenyl lower alkoxy lower alkoxy group and (15) a pyrrolidinyl carbonyl group. Also, the invention refers to a pharmaceutical composition, and a preventive and/or therapeutic agent based on the compound of formula (1), using the compound of formula (1), a method of treating or preventing the above diseases, to a method of preparing the compound of formula (1).

EFFECT: there are prepared new quinolone derivatives effective for treating and/or preventing the neurodegenerative diseases, diseases caused by neurological dysfunction, or diseases induced by deterioration of mitochondrial function.

11 cl, 1 tbl, 104 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to naphthalene carboxamide derivatives of general formula I which possess the properties of protein kinase or histone deacetylase inhibitors. The compounds can find application for preparing a drug for treating inflammatory diseases, autoimmune diseases, oncological disease, diseases of the nervous system and neurodegenerative diseases, allergies, asthma, cardiovascular diseases and metabolic diseases or disease related to hormonal diseases. In general formula I: , Z represents CH or N; each of the groups R1, R2 and R3 represents hydrogen, halogen, alkyl, alkoxy or trifluoromethyl; R4 represents or X represents a benzene ring or a pyridine ring; R5 represents one or more substitutes specified in a group consisting of hydrogen, halogen, alkyl, alkoxy or trifluoromethyl. The invention also refers to a method for preparing the above compounds, a pharmaceutical preparation and using them.

EFFECT: preparing the compounds which possess the properties of protein kinase or histone deacetylase inhibitors.

13 cl, 10 tbl, 6 dwg

FIELD: chemistry.

SUBSTANCE: claimed invention relates to field of organic chemistry, namely to novel compound of formula (I), where Y and Z, each independently, are selected from group, consisting of: a) phenyl, if necessary substituted with 1 or 2 R6; b) pyridine, imidazole, thiazole, furan, triazole, quinoline or imidazopyridine, if necessary substituted with 1 R6; and c) substituent, independently selected from group, consisting of hydrogen, C1-C6alkyl or pyperidine; R1, R2 and R3, each independently selected from group, consisting of hydrogen and halogen; A and B is each independently selected from hydrogen, OH and C1-C6alkyl; RA and RB are independently selected from group, consisting of hydrogen, C1-C6alkyl and C3-C8cycloalkyl; or RA and RB together with atom, to which they are attached, form 4-6-membered heterocycle, if necessary having additionally one heteroatom or functional heterogrpoup, selected from group, consisting of -O-, -NH, -N(C1-C6-alkyl)- and -NCO(C1-C6-alkyl)-, and 6-membered heterocycle can be additionally substituted with one or two C1-C6-alkyl groups; R4 and R5, each stands for hydrogen; and each R6 is selected from Br, Cl, F, I, C1-C6-alkyl, pyrrolidine, if necessary substituted with one C1-C6-alkyl, C1-C6alkoxy, halogen-C1-C6alkyl, hydroxyl-C1-C6alkylene, -(NRARB)C1-C6alkylene and (NRARB)carbonyl; or to its individual isomer, stereoisomer or enantiomer, or their mixture, if necessary pharmaceutically acceptable salt. Invention also relates to compound of formula (II), particular compounds of formula (I) and (II), pharmaceutical composition and industrial product based on compound of formula (I) and (II), method of treating said pathological conditions, method of obtaining formula (I) compound and to intermediate compound of formula 3.

EFFECT: novel compounds, useful as inhibitors of poly(ADP-ribose)polymerase, are obtained.

50 cl, 1 tbl, 159 ex

FIELD: chemistry.

SUBSTANCE: invention relates to formula compound or to its pharmaceutically acceptable salt, where R represents COOH or CH2OH. Invention also relates to pharmaceutical composition based on formula I, method of modulating CFTR activity in biological sample, based on application of formula I compound, method of treatment, based on application of formula I compound, set based on formula I compound.

EFFECT: obtained are novel derivatives of quinolin-4-one, useful as CFTR modulators.

18 cl, 1 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to field of organic chemistry, namely to method of obtaining compound of formula

1,

including condensation of carboxylic acid of formula

2

with aniline of formula

3 in presence of TZRŪ, where each R2 and R4 independently represents C1-6 alkyl with linear or branched chain, and each C1-6 alkyl with linear or branched chain is independently and optionally substituted with -OR'; each R5 represents OC(O)OR' or R4 and R5, taken together, form group , y represents 0, each R' represents C1-4 alkyl group, optionally substituted with one or more groups, selected from oxo and -O-C1-4-alkyl group. Invention also relates to intermediate compounds and methods of their obtaining.

EFFECT: elaborated is novel method of obtaining formula 1 compound, which can be useful as modulator of cystic fibrosis transmembrane conductance regulator (CFTR).

52 cl, 10 ex

FIELD: chemistry.

SUBSTANCE: claimed invention relates to field of organic chemistry, namely to novel quinolyl-containing compounds of hydroxamic acid of general formula (I), wherein each of V1 and V2 independently represents halogen; one of R and R' represents group Q, containing hydroxamic acid, and the other represents methoxy, wherein group Q, containing hydroxamic acid, is represented by formula ; A represents O; L represents C1-6alkyl; J represents NH, piperidinyl, or J is absent; X is absent; Y represents C1-6alkyl, or Y is absent. The invention also relates to method for obtaining formula (I) compound, pharmaceutical composition, based on formula (I) compound and its application for treatment of diseases, caused by proteinkinase and/or histone deacetylase activity.

EFFECT: novel compounds, which can be applied in cancer treatment, have been obtained.

25 cl, 7 dwg, 7 tbl, 45 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I and pharmaceutically acceptable salts thereof , where R is hydrogen, RO(OH)2, P(=O)(O-(C1-C6)alcylenphenyl)2 or P(=O)(OM)2; W represents 2-halogenphenyl, 3-halogenphenyl or 4-halogenphenyl; R5 is (C1-C6)alkoxy, hydroxyl or OR8; R6 is hydroxyl or (C1-C6)alkoxy; R7 represents hydrogen, hydroxyl or O-(C1-C6)alcylenphenyl; R8 represents a RO(OH)2, P(=O)(O-(C1-C6)alcylenphenyl)2 or P(=O)(OM)2, and m is monovalent metal ion; or where R is hydrogen, RO(OH)2, P(=O)(O-(C1-C6)alcylenphenyl)2 or P(=O)(OM)2; W represents 2-halogenphenyl, 3-halogenphenyl or 4-halogenphenyl; R5 represents hydrogen, (C1-C6)alkoxy, hydroxyl or OR8; R6 is (C1-C6)alkoxy; R7 is hydroxyl or O-(C1-C6)alcylenphenyl; R8 represents PO(OH)2, P(=O)(O-(C1-C6)alcylenphenyl)2 or P(=O)(OM)2, and m is monovalent metal ion. Disclosed compounds have anti-cancer activity. Invention also relates to compounds of formula I, radicals of which are presented in patent claim and to using pharmaceutical composition containing effective amount of compound of invention for treating cancer.

EFFECT: technical outcome is new compounds possessing anticancer activity.

17 cl, 23 dwg, 7 tbl, 4 ex

Up!