CA1340561C - Process for preparing ciprofloxacine - Google Patents
Process for preparing ciprofloxacineInfo
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- CA1340561C CA1340561C CA000602049A CA602049A CA1340561C CA 1340561 C CA1340561 C CA 1340561C CA 000602049 A CA000602049 A CA 000602049A CA 602049 A CA602049 A CA 602049A CA 1340561 C CA1340561 C CA 1340561C
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
The invention is concerned with a process for preparing ciprofloxacine of the formula (see fig.I) based on the reaction of 1-(2,4-dichloro-5-fluoro-phenyl)-1,3-butanedione with ethyl orthoformate, to give an enol ether which is reacted with cyclopropylamine, resulting in an enaminone, the cyclization of which provides a compound which is reacted with N-ethoxycar-bonylpiperazine, producing an intermediate, whose oxidation leads to an acid which provides ciprofloxacine by means of alkaline hydrolysis and neutralisation. Ciprofloxacine is a highly affective bactericidal agent against gram-positive and gram-negative bacteria.
Description
- 1. -1340~~~.
A PROCESS FOR PREPARING CIPROFLOXACINE
The invention refers to a process for preparing 1-cyclo-propyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-quinoline--3-carboxylic acid (ciprofloxacine) as per formula I) COOH
~t~ N ( I ~
the pharmaceutically acceptable acid addition salts and hydrates, thereof.
The subject compound is a bactericidal agent, recently introduced in therapeutics in certain countries and is highly effective against both gram-positive and gram-negative bacteria.
Spanish Patent No. 516.921 discloses a process for the preparation of the formula I compound) wherein starting from 2,4-dichloro-5-fluarobenzoyl chloride as per formula II
II
the formula I compound is obtained by means of a sequence of reactions involving seven steps, the first of which consists of acylation of diethyl malonate with theacid chloride of formula II in the presence of magnesium ethoxide prepared "in situ" from anhydrous ethanol and magnesium metal. There is also described the preparation of the Formula II starting material, which is not commercially available, starting from 2,4-dichloro-5-methylaniline using another synthetic route involving 5 steps.
Later, German Patent n~ 3.435.392 discloses a process for preparing 2,4-dichloro-5-fluorobenzoic acid as rer formula III, F / 00;i C1 ~1 (III) starting from 2,4-dichlorofluorobenzene as per formula IV, F
C ~' C1 (IV) a commercially available product, by means of a two phase sequence consisting of the acylation of the formula IV
compound with acetyl chloride and subsequent oxidative degra-dation of the resulting 2,4-dichloro-5-fluoro-acetophenone to achieve the said formula III acid. Finally the formula II
acid chloride is obtained by the action of thionyl chloride 13406:1 in a three phase sequence starting from 2,4-dichlorofluoroben-zene (IV), which represents an overall synthetic route of ten steps to obtain the formula I compound starting from the formula IV compound.
Thus, it has now been possible to establish a new process for preparing the formula I compound which is represented in the following reaction scheme:
1340~ti1 i~ i~
;: / CCH2CCH~ HC(OR~ )~ r C~'C~C~CH
A~ 0 / i 'CH 3( VII ) C1 ~ C1 ( VI ) R ~=Et, Me C'- ~ C1 ~ ORS
D-~~z (I
r ~ ~CH3 / C'C~C~CH
i 1 Dr~F ( n C1 ~ N base C1 ~ 1 C\~vH (VIII) (IX) E.t00C- ~H (X) I I C 'R / 00 H
L l ~I
N ~ IV ~ ~ t! N
N uiN J
Et04C
R = CEi3 (XI) (I) R - Ou (xII) 1340b1.
I.e., the process in accordance with the invention is characterized by the following steps:
a) reacting 1-(2,4-dichloro-5-fluorophenyl)-1,3-butanedione as per formula VI, C1 ~C1 (VI) with trimethyl or triethyl orthoformate in the presence of an excess of acetic anhydride to give an enol ether as per formula VII, CwC.~CwCE~
~~H (VII) C1 ~C1 ~' Oftl R1 being a methyl or ethyl group.
b) adding cyclopropylamine to the thus obtained enol ether, to give the enaminone as per formula VIII
(VIII) C ~C'C NCH
CH
C ~ C
c) cyclization of the enamine by heating in a high boiling point organic solvent in the presence of a base) to give the compound of formula IX) 13~0~~1 ll (i F
C ~C'_ (IX) d) reacting the thus obtained compound with N-ethoxycarbonyl piperazine as per formula X, Et00C- ~H (X) whereby the intermediate is obtained as per formula XI, F ~ ~ ~1 ~~ 3 .~ 1 I
~N h (XI) NJ
E t00C ~
e) oxidising of the intermediate in an alkaline medium to obtain the acid as per formula XII, F ~ COOH
~N
N J (XII) E 100C ~
and f) alkaline hydrolysis and neutralization whereby formula I compound is obtained.
The starting material for this new process) 1-(2,4-dichlo-ro-5-fluorophenyl)-1,3-butanedione of formula VI, has not been .. 134056.1 -described in scientific literature and was ubt;ained by cunden-sation of N-acetyl-2-pyrrolidine with 2,4-dichloru-5-fluuru--acetophenone of formula V;
C1 ~Cl (V) in the presence of a base such as sodium hydride in an inert solvent, for example ethyl ether, in accordance with the pro-cedure described by H. Stetter and W. Steinbeck for the synthesis of 1-phenyl-1,3-butanedione (See Chem. Ber., 103) 1088-1094 (1970)).
Alternatively) the butanedione as per formula VI was also prepared by acylation of the formula V compound with an excess of 2 mots of acetic anhydride in the presence of boron tri-fluoride ethyl acetate or acetic acid complexes thereof, in accordance with the procedure indicated in literature (See J. Am. Chem. Soc. 75, 5030 (1953)).
It has been found) in particular, that if the Formula V
acetophenone is acylated in the preparation of the Formula VI
starting material at moderate temperatures with an excess of two to four mols of acetic anhydride and in the presence of an exces of three to six muls of 40 wt~o boron trifluoride-acetic acid complex) excellent yields of Formula VI butanedione are obtained. Because of its simplicity, yield and high purity of the compound obtained, the use of this method is recommendable for the preparation of the said Formula VI starting material.
I340 ~b1 _8_ It may also be prepared by means of a Claisen condensation between formula V acetophenone and an excess of ethyl acetate in the presence of a base such as sodium methoxide, sodium ethoxide, sodium or s potassium tert-butoxide, sodium amidide or sodium hydride, at temperatures of between -10 and 60~C. This process, however, gave lower yields than the method indicated in the previous paragraph.
2,4-dichloro-5-fluoroacetophenone as per formula V
~o is a compound known in scientific literature (See Zh, Obshch Khim., 32, 3131 (1962), C.A. 58, 1l243 g), and is obtained by Friedel-Crafts acylation of 2,4 dichlorofluorobenzene, which is commercially available.
The proces of the invention affords advantages ~5 compared to methods indicated in the previously mentioned patents. First of a11, a 1,3-dicarbonyl substrate is obtained, capable of being condensed with trimethyl or triethyl orthoformate in only two steps starting from the formula IV 2,4-dichlorofluorobenzene, zo while with the other process mentioned in the previous patents, the analogous objective requires an elaborate five step sequence of reactions. Secondly, the number of steps necessary for obtaining ciprofloxacine (I) as from the formula IV compound is reduced to eight.
2s From an industrial viewpoint, both aspects represent a saving in power and manpower, as well as an improvement in the overall yield of the synthesis. On the other hand, the use of magnesium metal is avoided, which means greater manufacturing safety and adequacy, 3o particularly when working with much larger amounts.
- g _ Finally, a11 the reactants used in this novel process can be acduired freely on the market without the need for prior preparation of any of them.
The first step of the process for preparing the formula I
compound, i.e. the condensation of formula VI 1-(2,4-dichloro-5-fluorophenyl)-1,3-butanedione and an excess of triethyl urthoformate in the presence of more than two mols of acetic anhydride per mol of the initial compound) is conducted at temperatures of from l20~- to 15O~-C for a period of time of from one to three hours, in accordance with generally used methodology in reactions between alkyl orthoformates and 1,3-dicarbonyl compounds (See Methoden Organische Chemische, 4th Ed., Vol. VII, Page 49). After low pressure evaporation of the volatile material and the excess of reactants, the enol ether of formula VII is obtained which, without subsequent purification, is reacted with cyclopropylamine (step b) a~
temperatures of 0~- to 50~-C, in an inert solvent such as ethanol, methanol, isopropanol) methylene chloride, chloroform, benzene, toluene, etc., in order to obtain the formula VIII enaminone with an excellent yield.
When trimethyl orthoformate is used in step a), it is preferable for the Formula VI butanodione to be reacted with an excess of said trimethyl orthoformate in the presence of an excess of acetic anhydride to provide the corresponding enol ether in this case. The reaction occurs initially at the reflux temperature of the mixture for a period of time between one and three hours, after which) after distilling off some of ~3~O~b1 the more volatile by-products, the mixture is held at a temperature between 110~C and 150~C for from thirty minutes to three hours. Removal of the remaining volatile material by evaporation provides the enol ether s which, with the addition of cyclopropylamine under the conditions cited for step b), gives the Formula VIII
enaminone. The trimethyl orthoformate excess should preferably lie between one and two moles and the acetic anhydride excess between two and three moles per mol of ~o formula butanodione, with the molar amount of acetic anhydride being, at least, the sum of the other two components in the reaction.
This alternative possibility, relating to the use of trimethyl orthoformate, may represent savings on an ~s industrial scale, considering the lower cost of the trimethyl orthoformate than the triethyl orthoformate and considering the reduction of over 25% of the amount of the formerto be used in comparison with the latter, due to the molecular weight thereof.
zo Cyclization of formula VIII compound is carried out to obtain the formula IX compound (step c) by heating in a high boiling point organic solvent, such as N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl-sulphoxide, in the presence of a base such as potassium 2s carbonate, sodium carbonate, sodium methoxide, potassium tert-butoxide or sodium hydride, preferably potassium carbonate, at temperatures between 80~C and 180~C.
The 3-acetyl-4-oxo-quinoline of formula IX is condensed - 11 - 1340e1 (step d) with an excess of 2 to 4 cools ref N-ethuxycarbunyl-piperazine as per formula X, in the presence of an organic solvent of the same characteristics as those mentioned in ',;he previous paragraph) at temperatures lying between 80Q and 150~C
and reaction times lying between two and 10 hours, whereby formula XI intermediate is obtained with excellent yield.
The oxidation (step e) of the formula XI compound is carried out in water, or in mixtures thereof with miscible organic solvents, such as 1,4-dioxane or tetrahydrofurane) by the action of alkaline aqueous solutions of metal hypohalites, such as sodium hypochlorite or hypobromite, at temperatures between -10~- and 90~-C.
The oxidation may preferably be carried out by the action of an aqueous solution of commercial sodium hypochlorite on a solution of the said intermediate XI in a low molecular weight alcohol, fur example) methanol ur ethanol) at temperatures close to room temperature and reaction times lying between one and six hours.
Finally, hydrolysis of XII in the presence of an aqueous solution of alkaline hydroxide such as sodium hydroxide ur potassium hydroxide, leads to formula I compound being obtained with good yields. Water or mixtures thereof with a low molecular weight alcohol can be used as reaction solvent.
Reaction is carried out at reflux temperature of the solvent used) over a time of between one and four hours.
In order to provide a clear understanding of a11 the foregoing) hereunder some non-limiting examples of the inventive process are described.
134n~~~.
EXAi~fPLE 1. Preparation of starting material:
1-(2,4-dichloru-5-fluruphenyl-1,3-butanP~iune (VI).
31.05 g (0.15 mul) of 2,4-dichluru-5-fluuroacetophenone (V) were added at room temperature to 112.7 g of a 40 wt%
solution of boron trifluuride in acetic acid (IiF3-2 CH3COOH
complex). The solution was stirred for one hour at room temperature and 45.9 g (0.45 mol} of acetic anhydride were added over 10 minutes. The mixture was heated at 40oC fur 8 hours and then held for a further 16 hours at room temperature with stirring. The crystalline slurry was filtered in an inert atmosphere and well drained. Approximately 46 g of the boron difluoride complex VI were obtained. The moist solid was poured over a solution of 73.8 g of anhydrous sodium acetate dissolved in 6?5 ml of water and the mixture was heated at reflux for 90 minutes. It was extracted three times with n-hexane (200, 120 and 100 ml) and the organic extract was washed with 1S0 ml of a saturated sodium bicarbonate solution.
It was dried with anhydrous sodium sulphate, filtered and the solvent was evaporated off to give 24,7 g of the compound of Formal a VIII .
After 5 days at room temperature) the reaction liquors had deposited a further 6.65 g of the boron difluoride complex VI which) when treated in the same way as the main fraction, gave a further 3.8 g of the compound of the title, therefore, 28.5 g of VI (Yield 76~0} in the form of a whitish-pink solid.
The spectroscopic data show that the formula VI compound is totally enolised, both in solid state and in solution.
A sample crystallised from n-hexane gave a melting point of 68-69''C.
- 13 - .3405b1 Preparation of starting material: 1-(2,4-dichloro-5-fluorophe-nyI)-1,3-butanedione (VI).
1l,8 g (0.295 mols) of 60% sodium hydride in mineral oil, and 80 mI of n-hexane were placed in a 500 ml three necked spherical flask, fitted with an addition funnel, reflex refri-Berated and nitrogen blanket. After stirring for ten minutes the solvent is poured off. The procedure was repeated twice again with 80 m1 of n-hexane on each occasion, and thereafter 100 ml of absolute ethyl ether were added and the solvent was poured again. 230 ml of absolute ethyl ether were added and over the slurry a mixture of 30,3 g (0,146 mols) of 2,4-dichloro-5-fluoracetophenone and 18,6 g (0,146 mols) of N-acetyl-2-pyrrolidone were added dropwise at room temperature.
The mixture was stirred at room temperature for an hour and then heated to reflex for three hours. It was then cooled to -5~C and 65 ml of 30% acetic acid were carefully added. The ethereal phase was decanted) washed with 100 ml of a 5%
sodium bicarbonate solution and then with 50 ml of water then dried with anhydrous sodium sulphate. After filtration and evaporation of the solvent, the resulting residue was purified by low pressure distillation. The fraction.distilling at 118-133~-C and 0,15 mm was collected) whereby 27,7 g (yield 76%) of 2,4-dichloro-5-fluorophenyl)-1,3-butanedione were obtained with sufficient purity for it to be used in the following steps.
L' V A M T7 T L' 7 Preparation of 3-(2,4-dichloro-5-fluorobenzoyl)-4-ethoxy-3-buten-2-one (VII). (R1=Et) A three necked spherical flask fitted for a distillation were placed with 27.4 g (0.l1 mol) of 1-(2,4-dichloro-5-fluorophenyl)-1,3-butanedione, 23.7 g (0.16 mol) of triethyl orthoformate and 27.5 g. (0.25 s mol) of acetic anhydride. The mixture was heated slowly, distilling at the same time the volatile reaction products until internal temperature reached 140~C. This temperature was held for two hours, and then left to cool and the residual volatile components were distilled io off at 95-100~C and 2-3 mm Hg. In this way 33.5 g of a crude residue were obtained, corresponding to the tital compound and usable in the following phase without any purification whatsoever. (Yield 99.8%).
15 Preparation of 4-cyclopropylamine)-3-(2,4-dichloro-5-fluorobenzoyl)-3-buten-2-one (VIII) 6,3 g (0.11 mol) of cyclopropylamine were added, dropwise with stirring to a solution cooled to 0~C of 33.5 g (0.11 mol) of crude 3-(2,4-dichloro-5-zo fluorobenzoyl)-4-ethoxy-3-buten-2-one in 100 ml of absolute ethanol in such a way that the temperature did not exceed 20~C. When the addition was over an abundant precipitate forms. The suspension was stirred at room temperature for 2 hours and then 80 ml of water were z5 slowly added and it was cooled to 0~C. The mixture was then filtered and the solid washed with 30 ml of a mixture of equal parts of ethanol and water. 32 g of compound VIII were produced (yield 92%).
1340~~i1 rvnn~rnr r. c Preparation of 3-(2,4-dichloru-5-fluorobenzuyl)-4-methoxy-3-buten-2-one (VII, R1 - Me5.
In a three necked spherical flask were placed 23 g (92.3 mmols) of 1-(2,4-dichloro-5-fluorophenyl)-1,3-butanedione, 14.7 g (138.5 mmols) of trimethyl orthoformate and 23.6 g (231 mmols) of acetic anhydride. The mixture was heated under reflux for 2 hours, A mixture of methyl acetate and acetic acid were distilled until an internal temperature of 130oC was reached. This temperature was held for one hour, after which heating was removed and vacuum (1-2 mmHg) was applied to remove the volatile residues. 26.1 g (Yield 97~) of the compound of the title were obtained in form of a dark brown oil, used unpurified in the following step.
FXAMPT.F F, Preparation of 4-cyclopropylamino)-3-(2,4-dichloro-5-fluoro-benzoyl)-3-buten-2-one (VIII).
The oil obtained in the previous step (26.1 g, 89.6 mmols) was dissolved in 50 ml of methanol. The solution was cooled to 5oC and 5.4 g (94,5 mmols) of cyclopropylamine were added dropwise while the temperature was held to not exceed 15QC. The crystalline suspension was stirred for one hour at room temperature. It was cooled to OoC and held at this temperature for30 minutes. It was filtered) washed with 10 ml of cold methanol and dried in a current of air. 21.5 g (Yield 76io) of a crystalline solid were obtained, with m.p.
122-124uC) corresponding to the Formula VII compound.
... 1340W1 Preparation of 3-acetyl-1-cyclopropyl-7-chloro-6-fluoro-1 4-dihydro-4-oxoquinoline (IX).
A mixture of 36 g (113.8 mmols) of the compound of formula VIII, 17.4 g (126 mmols) of finely divided anhydrous potassium carbonate and 110 ml of N,N
dimethylformamide was stirred and heated at 130~C for 2 hours. It was cooled to room temperature and 32 ml of water were added dropwise. The slurry was cooled 15~C
to and filtered. The moist solid (58 g) was suspended in 200 ml of water and stirred at room temperature for 15 minutes . It was filtered again and washed with 50 ml of water. It was dried under a current of air to give 27 g (Yield 85%) of the compound of the title, under the form Of a brown solid, with m.p. 177-179~C.
Preparation of 3-acetyl-1-cyclopropyl-7-(4-ethoxycar-bonyl-1-piperacinyl)-6-fluoro-1,4-dihydro-4-oxoctuinoline XI
zo A mixture of 20 g (7l.5 mmols) of the Formula IX
intermediate, 80 ml of N,N-dimethylacetamide and 42 g (266 mmols) of N-ethoxycarbonylpiperazine (X) were heated at 150~C for 15 hours. The mixture was cooled to 10-15~C and 340 ml of water were added at this z5 temperature, with vigorous stirring, causing crystallization. The precipitate was filtered, was washed with water and dried. 24 g of the raw compound of Formula XI were obtained (Yield 84%) in the form of a brown solid which was purified by filtration through 3o silica gel, using a mixture of chloroform-methanol (15:1) as eluent.
X
~.~40~~1 Preparation of 1-cyclopropyl-7-(4-ethoxycarbonyl-1-pip-erazinyl)-6-fluoro-1,4-dihydro-4-oxoctuinoline-3-carboxYlic acid (XII).
120 ml of a 15% aqueous solution of sodium hypochlorite were added over 30 minutes with stirring to a solution of 20 g (49.8 mmols) of the intermediate of Formula XI in 160 ml of absolute ethanol, the temperature being held to between 20~C and 25~C. The ~o reaction mixture was stirred for a further 3 hours at the same temperature, 400 ml of water were added and the major portion of ethanol was removed by low pressure distillation, without the temperature of the mixture being allowed to exceed 35~C. The insoluble material was 5 removed by filtration and washed with water. 10 ml of a 40% aqueous solution of sodium bisulfate were added to the remaining solution and the solution was acidulated with concentrated HC1. The precipitate was filtered, washed with water and dried. 12.4 g (Yield 64%) were zo obtained of the compound of Formula XII, in the form of a yellowish solid having a melting point of 296-304~C
with decomposition.
Preparation of 1-cvclopropyl-7-(1-piperacinyl)-6-fluoro zs 1 4-dih~dro-4-oxoauinoline-3-carboxylic acid (I) (Cipro floxacine).
l0 g (25 mmols) of the acid of Formula XII were added to a solution of 5.6 g (90 mmols) of 90% potassium hydroxide in 140 ml of water. The mixture was stirred 3o and heated under reflux for 4 hours. It was allowed to cool and the solution y..
- 18 - 13~~,ri~
was stirred fur half an hour with 2 g of activated carbon. It was filtered and 160 ml of 1N HC1 were added to the filtrate.
The opalescent solution was clarified by filtration and the pH
was adjusted to 7.2 by addition of 10% ammonium hydroxide. The precipitate was cooled to S-lOoC for 2 hours) was filtered and dried at 80oC under Vacuum. 4.1 g of ciprofloxacine (I) were obtained as a solid, with m.p. 250-255oC with decomposition (Yield 52/).
A PROCESS FOR PREPARING CIPROFLOXACINE
The invention refers to a process for preparing 1-cyclo-propyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-quinoline--3-carboxylic acid (ciprofloxacine) as per formula I) COOH
~t~ N ( I ~
the pharmaceutically acceptable acid addition salts and hydrates, thereof.
The subject compound is a bactericidal agent, recently introduced in therapeutics in certain countries and is highly effective against both gram-positive and gram-negative bacteria.
Spanish Patent No. 516.921 discloses a process for the preparation of the formula I compound) wherein starting from 2,4-dichloro-5-fluarobenzoyl chloride as per formula II
II
the formula I compound is obtained by means of a sequence of reactions involving seven steps, the first of which consists of acylation of diethyl malonate with theacid chloride of formula II in the presence of magnesium ethoxide prepared "in situ" from anhydrous ethanol and magnesium metal. There is also described the preparation of the Formula II starting material, which is not commercially available, starting from 2,4-dichloro-5-methylaniline using another synthetic route involving 5 steps.
Later, German Patent n~ 3.435.392 discloses a process for preparing 2,4-dichloro-5-fluorobenzoic acid as rer formula III, F / 00;i C1 ~1 (III) starting from 2,4-dichlorofluorobenzene as per formula IV, F
C ~' C1 (IV) a commercially available product, by means of a two phase sequence consisting of the acylation of the formula IV
compound with acetyl chloride and subsequent oxidative degra-dation of the resulting 2,4-dichloro-5-fluoro-acetophenone to achieve the said formula III acid. Finally the formula II
acid chloride is obtained by the action of thionyl chloride 13406:1 in a three phase sequence starting from 2,4-dichlorofluoroben-zene (IV), which represents an overall synthetic route of ten steps to obtain the formula I compound starting from the formula IV compound.
Thus, it has now been possible to establish a new process for preparing the formula I compound which is represented in the following reaction scheme:
1340~ti1 i~ i~
;: / CCH2CCH~ HC(OR~ )~ r C~'C~C~CH
A~ 0 / i 'CH 3( VII ) C1 ~ C1 ( VI ) R ~=Et, Me C'- ~ C1 ~ ORS
D-~~z (I
r ~ ~CH3 / C'C~C~CH
i 1 Dr~F ( n C1 ~ N base C1 ~ 1 C\~vH (VIII) (IX) E.t00C- ~H (X) I I C 'R / 00 H
L l ~I
N ~ IV ~ ~ t! N
N uiN J
Et04C
R = CEi3 (XI) (I) R - Ou (xII) 1340b1.
I.e., the process in accordance with the invention is characterized by the following steps:
a) reacting 1-(2,4-dichloro-5-fluorophenyl)-1,3-butanedione as per formula VI, C1 ~C1 (VI) with trimethyl or triethyl orthoformate in the presence of an excess of acetic anhydride to give an enol ether as per formula VII, CwC.~CwCE~
~~H (VII) C1 ~C1 ~' Oftl R1 being a methyl or ethyl group.
b) adding cyclopropylamine to the thus obtained enol ether, to give the enaminone as per formula VIII
(VIII) C ~C'C NCH
CH
C ~ C
c) cyclization of the enamine by heating in a high boiling point organic solvent in the presence of a base) to give the compound of formula IX) 13~0~~1 ll (i F
C ~C'_ (IX) d) reacting the thus obtained compound with N-ethoxycarbonyl piperazine as per formula X, Et00C- ~H (X) whereby the intermediate is obtained as per formula XI, F ~ ~ ~1 ~~ 3 .~ 1 I
~N h (XI) NJ
E t00C ~
e) oxidising of the intermediate in an alkaline medium to obtain the acid as per formula XII, F ~ COOH
~N
N J (XII) E 100C ~
and f) alkaline hydrolysis and neutralization whereby formula I compound is obtained.
The starting material for this new process) 1-(2,4-dichlo-ro-5-fluorophenyl)-1,3-butanedione of formula VI, has not been .. 134056.1 -described in scientific literature and was ubt;ained by cunden-sation of N-acetyl-2-pyrrolidine with 2,4-dichloru-5-fluuru--acetophenone of formula V;
C1 ~Cl (V) in the presence of a base such as sodium hydride in an inert solvent, for example ethyl ether, in accordance with the pro-cedure described by H. Stetter and W. Steinbeck for the synthesis of 1-phenyl-1,3-butanedione (See Chem. Ber., 103) 1088-1094 (1970)).
Alternatively) the butanedione as per formula VI was also prepared by acylation of the formula V compound with an excess of 2 mots of acetic anhydride in the presence of boron tri-fluoride ethyl acetate or acetic acid complexes thereof, in accordance with the procedure indicated in literature (See J. Am. Chem. Soc. 75, 5030 (1953)).
It has been found) in particular, that if the Formula V
acetophenone is acylated in the preparation of the Formula VI
starting material at moderate temperatures with an excess of two to four mols of acetic anhydride and in the presence of an exces of three to six muls of 40 wt~o boron trifluoride-acetic acid complex) excellent yields of Formula VI butanedione are obtained. Because of its simplicity, yield and high purity of the compound obtained, the use of this method is recommendable for the preparation of the said Formula VI starting material.
I340 ~b1 _8_ It may also be prepared by means of a Claisen condensation between formula V acetophenone and an excess of ethyl acetate in the presence of a base such as sodium methoxide, sodium ethoxide, sodium or s potassium tert-butoxide, sodium amidide or sodium hydride, at temperatures of between -10 and 60~C. This process, however, gave lower yields than the method indicated in the previous paragraph.
2,4-dichloro-5-fluoroacetophenone as per formula V
~o is a compound known in scientific literature (See Zh, Obshch Khim., 32, 3131 (1962), C.A. 58, 1l243 g), and is obtained by Friedel-Crafts acylation of 2,4 dichlorofluorobenzene, which is commercially available.
The proces of the invention affords advantages ~5 compared to methods indicated in the previously mentioned patents. First of a11, a 1,3-dicarbonyl substrate is obtained, capable of being condensed with trimethyl or triethyl orthoformate in only two steps starting from the formula IV 2,4-dichlorofluorobenzene, zo while with the other process mentioned in the previous patents, the analogous objective requires an elaborate five step sequence of reactions. Secondly, the number of steps necessary for obtaining ciprofloxacine (I) as from the formula IV compound is reduced to eight.
2s From an industrial viewpoint, both aspects represent a saving in power and manpower, as well as an improvement in the overall yield of the synthesis. On the other hand, the use of magnesium metal is avoided, which means greater manufacturing safety and adequacy, 3o particularly when working with much larger amounts.
- g _ Finally, a11 the reactants used in this novel process can be acduired freely on the market without the need for prior preparation of any of them.
The first step of the process for preparing the formula I
compound, i.e. the condensation of formula VI 1-(2,4-dichloro-5-fluorophenyl)-1,3-butanedione and an excess of triethyl urthoformate in the presence of more than two mols of acetic anhydride per mol of the initial compound) is conducted at temperatures of from l20~- to 15O~-C for a period of time of from one to three hours, in accordance with generally used methodology in reactions between alkyl orthoformates and 1,3-dicarbonyl compounds (See Methoden Organische Chemische, 4th Ed., Vol. VII, Page 49). After low pressure evaporation of the volatile material and the excess of reactants, the enol ether of formula VII is obtained which, without subsequent purification, is reacted with cyclopropylamine (step b) a~
temperatures of 0~- to 50~-C, in an inert solvent such as ethanol, methanol, isopropanol) methylene chloride, chloroform, benzene, toluene, etc., in order to obtain the formula VIII enaminone with an excellent yield.
When trimethyl orthoformate is used in step a), it is preferable for the Formula VI butanodione to be reacted with an excess of said trimethyl orthoformate in the presence of an excess of acetic anhydride to provide the corresponding enol ether in this case. The reaction occurs initially at the reflux temperature of the mixture for a period of time between one and three hours, after which) after distilling off some of ~3~O~b1 the more volatile by-products, the mixture is held at a temperature between 110~C and 150~C for from thirty minutes to three hours. Removal of the remaining volatile material by evaporation provides the enol ether s which, with the addition of cyclopropylamine under the conditions cited for step b), gives the Formula VIII
enaminone. The trimethyl orthoformate excess should preferably lie between one and two moles and the acetic anhydride excess between two and three moles per mol of ~o formula butanodione, with the molar amount of acetic anhydride being, at least, the sum of the other two components in the reaction.
This alternative possibility, relating to the use of trimethyl orthoformate, may represent savings on an ~s industrial scale, considering the lower cost of the trimethyl orthoformate than the triethyl orthoformate and considering the reduction of over 25% of the amount of the formerto be used in comparison with the latter, due to the molecular weight thereof.
zo Cyclization of formula VIII compound is carried out to obtain the formula IX compound (step c) by heating in a high boiling point organic solvent, such as N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl-sulphoxide, in the presence of a base such as potassium 2s carbonate, sodium carbonate, sodium methoxide, potassium tert-butoxide or sodium hydride, preferably potassium carbonate, at temperatures between 80~C and 180~C.
The 3-acetyl-4-oxo-quinoline of formula IX is condensed - 11 - 1340e1 (step d) with an excess of 2 to 4 cools ref N-ethuxycarbunyl-piperazine as per formula X, in the presence of an organic solvent of the same characteristics as those mentioned in ',;he previous paragraph) at temperatures lying between 80Q and 150~C
and reaction times lying between two and 10 hours, whereby formula XI intermediate is obtained with excellent yield.
The oxidation (step e) of the formula XI compound is carried out in water, or in mixtures thereof with miscible organic solvents, such as 1,4-dioxane or tetrahydrofurane) by the action of alkaline aqueous solutions of metal hypohalites, such as sodium hypochlorite or hypobromite, at temperatures between -10~- and 90~-C.
The oxidation may preferably be carried out by the action of an aqueous solution of commercial sodium hypochlorite on a solution of the said intermediate XI in a low molecular weight alcohol, fur example) methanol ur ethanol) at temperatures close to room temperature and reaction times lying between one and six hours.
Finally, hydrolysis of XII in the presence of an aqueous solution of alkaline hydroxide such as sodium hydroxide ur potassium hydroxide, leads to formula I compound being obtained with good yields. Water or mixtures thereof with a low molecular weight alcohol can be used as reaction solvent.
Reaction is carried out at reflux temperature of the solvent used) over a time of between one and four hours.
In order to provide a clear understanding of a11 the foregoing) hereunder some non-limiting examples of the inventive process are described.
134n~~~.
EXAi~fPLE 1. Preparation of starting material:
1-(2,4-dichloru-5-fluruphenyl-1,3-butanP~iune (VI).
31.05 g (0.15 mul) of 2,4-dichluru-5-fluuroacetophenone (V) were added at room temperature to 112.7 g of a 40 wt%
solution of boron trifluuride in acetic acid (IiF3-2 CH3COOH
complex). The solution was stirred for one hour at room temperature and 45.9 g (0.45 mol} of acetic anhydride were added over 10 minutes. The mixture was heated at 40oC fur 8 hours and then held for a further 16 hours at room temperature with stirring. The crystalline slurry was filtered in an inert atmosphere and well drained. Approximately 46 g of the boron difluoride complex VI were obtained. The moist solid was poured over a solution of 73.8 g of anhydrous sodium acetate dissolved in 6?5 ml of water and the mixture was heated at reflux for 90 minutes. It was extracted three times with n-hexane (200, 120 and 100 ml) and the organic extract was washed with 1S0 ml of a saturated sodium bicarbonate solution.
It was dried with anhydrous sodium sulphate, filtered and the solvent was evaporated off to give 24,7 g of the compound of Formal a VIII .
After 5 days at room temperature) the reaction liquors had deposited a further 6.65 g of the boron difluoride complex VI which) when treated in the same way as the main fraction, gave a further 3.8 g of the compound of the title, therefore, 28.5 g of VI (Yield 76~0} in the form of a whitish-pink solid.
The spectroscopic data show that the formula VI compound is totally enolised, both in solid state and in solution.
A sample crystallised from n-hexane gave a melting point of 68-69''C.
- 13 - .3405b1 Preparation of starting material: 1-(2,4-dichloro-5-fluorophe-nyI)-1,3-butanedione (VI).
1l,8 g (0.295 mols) of 60% sodium hydride in mineral oil, and 80 mI of n-hexane were placed in a 500 ml three necked spherical flask, fitted with an addition funnel, reflex refri-Berated and nitrogen blanket. After stirring for ten minutes the solvent is poured off. The procedure was repeated twice again with 80 m1 of n-hexane on each occasion, and thereafter 100 ml of absolute ethyl ether were added and the solvent was poured again. 230 ml of absolute ethyl ether were added and over the slurry a mixture of 30,3 g (0,146 mols) of 2,4-dichloro-5-fluoracetophenone and 18,6 g (0,146 mols) of N-acetyl-2-pyrrolidone were added dropwise at room temperature.
The mixture was stirred at room temperature for an hour and then heated to reflex for three hours. It was then cooled to -5~C and 65 ml of 30% acetic acid were carefully added. The ethereal phase was decanted) washed with 100 ml of a 5%
sodium bicarbonate solution and then with 50 ml of water then dried with anhydrous sodium sulphate. After filtration and evaporation of the solvent, the resulting residue was purified by low pressure distillation. The fraction.distilling at 118-133~-C and 0,15 mm was collected) whereby 27,7 g (yield 76%) of 2,4-dichloro-5-fluorophenyl)-1,3-butanedione were obtained with sufficient purity for it to be used in the following steps.
L' V A M T7 T L' 7 Preparation of 3-(2,4-dichloro-5-fluorobenzoyl)-4-ethoxy-3-buten-2-one (VII). (R1=Et) A three necked spherical flask fitted for a distillation were placed with 27.4 g (0.l1 mol) of 1-(2,4-dichloro-5-fluorophenyl)-1,3-butanedione, 23.7 g (0.16 mol) of triethyl orthoformate and 27.5 g. (0.25 s mol) of acetic anhydride. The mixture was heated slowly, distilling at the same time the volatile reaction products until internal temperature reached 140~C. This temperature was held for two hours, and then left to cool and the residual volatile components were distilled io off at 95-100~C and 2-3 mm Hg. In this way 33.5 g of a crude residue were obtained, corresponding to the tital compound and usable in the following phase without any purification whatsoever. (Yield 99.8%).
15 Preparation of 4-cyclopropylamine)-3-(2,4-dichloro-5-fluorobenzoyl)-3-buten-2-one (VIII) 6,3 g (0.11 mol) of cyclopropylamine were added, dropwise with stirring to a solution cooled to 0~C of 33.5 g (0.11 mol) of crude 3-(2,4-dichloro-5-zo fluorobenzoyl)-4-ethoxy-3-buten-2-one in 100 ml of absolute ethanol in such a way that the temperature did not exceed 20~C. When the addition was over an abundant precipitate forms. The suspension was stirred at room temperature for 2 hours and then 80 ml of water were z5 slowly added and it was cooled to 0~C. The mixture was then filtered and the solid washed with 30 ml of a mixture of equal parts of ethanol and water. 32 g of compound VIII were produced (yield 92%).
1340~~i1 rvnn~rnr r. c Preparation of 3-(2,4-dichloru-5-fluorobenzuyl)-4-methoxy-3-buten-2-one (VII, R1 - Me5.
In a three necked spherical flask were placed 23 g (92.3 mmols) of 1-(2,4-dichloro-5-fluorophenyl)-1,3-butanedione, 14.7 g (138.5 mmols) of trimethyl orthoformate and 23.6 g (231 mmols) of acetic anhydride. The mixture was heated under reflux for 2 hours, A mixture of methyl acetate and acetic acid were distilled until an internal temperature of 130oC was reached. This temperature was held for one hour, after which heating was removed and vacuum (1-2 mmHg) was applied to remove the volatile residues. 26.1 g (Yield 97~) of the compound of the title were obtained in form of a dark brown oil, used unpurified in the following step.
FXAMPT.F F, Preparation of 4-cyclopropylamino)-3-(2,4-dichloro-5-fluoro-benzoyl)-3-buten-2-one (VIII).
The oil obtained in the previous step (26.1 g, 89.6 mmols) was dissolved in 50 ml of methanol. The solution was cooled to 5oC and 5.4 g (94,5 mmols) of cyclopropylamine were added dropwise while the temperature was held to not exceed 15QC. The crystalline suspension was stirred for one hour at room temperature. It was cooled to OoC and held at this temperature for30 minutes. It was filtered) washed with 10 ml of cold methanol and dried in a current of air. 21.5 g (Yield 76io) of a crystalline solid were obtained, with m.p.
122-124uC) corresponding to the Formula VII compound.
... 1340W1 Preparation of 3-acetyl-1-cyclopropyl-7-chloro-6-fluoro-1 4-dihydro-4-oxoquinoline (IX).
A mixture of 36 g (113.8 mmols) of the compound of formula VIII, 17.4 g (126 mmols) of finely divided anhydrous potassium carbonate and 110 ml of N,N
dimethylformamide was stirred and heated at 130~C for 2 hours. It was cooled to room temperature and 32 ml of water were added dropwise. The slurry was cooled 15~C
to and filtered. The moist solid (58 g) was suspended in 200 ml of water and stirred at room temperature for 15 minutes . It was filtered again and washed with 50 ml of water. It was dried under a current of air to give 27 g (Yield 85%) of the compound of the title, under the form Of a brown solid, with m.p. 177-179~C.
Preparation of 3-acetyl-1-cyclopropyl-7-(4-ethoxycar-bonyl-1-piperacinyl)-6-fluoro-1,4-dihydro-4-oxoctuinoline XI
zo A mixture of 20 g (7l.5 mmols) of the Formula IX
intermediate, 80 ml of N,N-dimethylacetamide and 42 g (266 mmols) of N-ethoxycarbonylpiperazine (X) were heated at 150~C for 15 hours. The mixture was cooled to 10-15~C and 340 ml of water were added at this z5 temperature, with vigorous stirring, causing crystallization. The precipitate was filtered, was washed with water and dried. 24 g of the raw compound of Formula XI were obtained (Yield 84%) in the form of a brown solid which was purified by filtration through 3o silica gel, using a mixture of chloroform-methanol (15:1) as eluent.
X
~.~40~~1 Preparation of 1-cyclopropyl-7-(4-ethoxycarbonyl-1-pip-erazinyl)-6-fluoro-1,4-dihydro-4-oxoctuinoline-3-carboxYlic acid (XII).
120 ml of a 15% aqueous solution of sodium hypochlorite were added over 30 minutes with stirring to a solution of 20 g (49.8 mmols) of the intermediate of Formula XI in 160 ml of absolute ethanol, the temperature being held to between 20~C and 25~C. The ~o reaction mixture was stirred for a further 3 hours at the same temperature, 400 ml of water were added and the major portion of ethanol was removed by low pressure distillation, without the temperature of the mixture being allowed to exceed 35~C. The insoluble material was 5 removed by filtration and washed with water. 10 ml of a 40% aqueous solution of sodium bisulfate were added to the remaining solution and the solution was acidulated with concentrated HC1. The precipitate was filtered, washed with water and dried. 12.4 g (Yield 64%) were zo obtained of the compound of Formula XII, in the form of a yellowish solid having a melting point of 296-304~C
with decomposition.
Preparation of 1-cvclopropyl-7-(1-piperacinyl)-6-fluoro zs 1 4-dih~dro-4-oxoauinoline-3-carboxylic acid (I) (Cipro floxacine).
l0 g (25 mmols) of the acid of Formula XII were added to a solution of 5.6 g (90 mmols) of 90% potassium hydroxide in 140 ml of water. The mixture was stirred 3o and heated under reflux for 4 hours. It was allowed to cool and the solution y..
- 18 - 13~~,ri~
was stirred fur half an hour with 2 g of activated carbon. It was filtered and 160 ml of 1N HC1 were added to the filtrate.
The opalescent solution was clarified by filtration and the pH
was adjusted to 7.2 by addition of 10% ammonium hydroxide. The precipitate was cooled to S-lOoC for 2 hours) was filtered and dried at 80oC under Vacuum. 4.1 g of ciprofloxacine (I) were obtained as a solid, with m.p. 250-255oC with decomposition (Yield 52/).
Claims (18)
1. A process for the preparation of 1-cyclo-propyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-quinoline-3-carboxylic acid of formula (I):
and pharmaceutically acceptable acid addition salts or hydrates thereof, which comprises the steps of:
a) reacting 1-(2,5-dichloro-5-fluorophenyl)-1,3-butanedione of formula (VI):
with methyl or triethyl orthoformate in the presence of acetic anhydride to produce an enol ether having the formula (VII):
wherein R1 is a methyl or ethyl group;
b) adding cyclopropylamine to the enol ether of formula (VII) to produce an enaminone having the formula (VIII):
c) cyclizing the enaminone of formula (VIII) by heating in an organic solvent and in the presence of a base, to produce a compound having the formula (IX):
d) reacting the compound of formula (IX) with N-ethoxycarbonylpiperazine of formula (X):
to produce an intermediate having the formula (XI):
e) oxidizing the intermediate of formula (XI) in an alkaline medium to obtain an acid having the formula (XII):
f) subjecting the acid of formula (XII) to an alkaline hydrolysis and neutralization, to obtain the desired compound of formula (I); and g) if desired, converting the compound of formula (I) thus obtained into a corresponding pharmaceutically acceptable acid addition salt or hydrate.
and pharmaceutically acceptable acid addition salts or hydrates thereof, which comprises the steps of:
a) reacting 1-(2,5-dichloro-5-fluorophenyl)-1,3-butanedione of formula (VI):
with methyl or triethyl orthoformate in the presence of acetic anhydride to produce an enol ether having the formula (VII):
wherein R1 is a methyl or ethyl group;
b) adding cyclopropylamine to the enol ether of formula (VII) to produce an enaminone having the formula (VIII):
c) cyclizing the enaminone of formula (VIII) by heating in an organic solvent and in the presence of a base, to produce a compound having the formula (IX):
d) reacting the compound of formula (IX) with N-ethoxycarbonylpiperazine of formula (X):
to produce an intermediate having the formula (XI):
e) oxidizing the intermediate of formula (XI) in an alkaline medium to obtain an acid having the formula (XII):
f) subjecting the acid of formula (XII) to an alkaline hydrolysis and neutralization, to obtain the desired compound of formula (I); and g) if desired, converting the compound of formula (I) thus obtained into a corresponding pharmaceutically acceptable acid addition salt or hydrate.
2. The process of claim 1, characterized in that in step (a) the butanedione of formula (VI) is reacted with trimethyl orthoformate in the presence of acetic anhydride.
3. The process of claim 2, characterized in that said reaction is conducted initially at the reflux temperature of the mixture for a period of one to three hours after which, after removal by distillation of part of the more volatile by-products, the mixture is maintained at a temperature comprised between 110° and 150°C for a period of from thirty minutes to three hours.
4. The process of claim 2 or 3, characterized in that the butadione of formula (VI) is reacted with an excess of 1 to 2 mols of trimethyl orthoformate in the presence of an excess of 2 to 3 mols of acetic anhydride, per mol of butadione of formula (VI), the molar amount of acetic anhydride being at least the sum of the molar amount of the trimethyl orthoformate and the molar amount of the compound of formula (VI).
5. The process of claim 1, characterized in that the compound of formula (VI) is prepared from acetophenone of formula (V):
by reaction with acetic anhydride in the presence of boron trifluoride or complexes thereof with ethyl acetate or acetic acid.
by reaction with acetic anhydride in the presence of boron trifluoride or complexes thereof with ethyl acetate or acetic acid.
6. The process of claim 5, characterized in that the acetophenone of formula (V) is reacted with an excess of 2 to 4 mols of acetic anhydride in the presence of an excess of 3 to 6 mols of boron trifluoride, per mol of acetophenone of formula (V).
7. The process of claim 1, characterized in that the reaction in step (a) is carried out at a temperature between 110° and 150°C and using 2 to 4 mols of acetic anhydride per mol of compounds of formula (VI).
8. The process of claim 1, characterized in that the reaction in step (b) is carried out at a temperature between 0° and 50°C in an inert organic solvent.
9. The process of claim 8, characterized in that said inert organic solvent is selected from the group consisting of ethanol, methanol, isopropanol, methylene chloride, chloroform, benzene and toluene.
10. The process of claim 1, characterized in that cyclization in step (c) is conducted by heating in an organic solvent in the presence of a base and at a temperature between 80° and 180°C.
11. The process of claim 10, characterized in that said base is selected from the group consisting of potassium carbonate, sodium carbonate, sodium methoxide, potassium tert-butoxide and sodium hydride.
12. The process of claim 1, characterized in that the reaction in step (d) is carried out using an excess of two to four mols of the compounds of formula (X), in an organic solvent and at a temperature between 80° and 150°C.
13. The process of claim 10 or 12, characterized in that said organic solvent is selected from the group consisting of N,N-dimethylformamide, N,N-dimethylacetamide and di-methylsulphoxide.
14. The process of claim 1, characterized in that the oxidation in step (e) is effected in an alkaline aqueous medium or mixture thereof with a water miscible organic solvent, by the action of an alkali hypohalite.
15. The process of claim 14, characterized in that said organic solvent is methanol or ethanol and said alkali hypohalite is sodium hypochlorite.
16. The process of claim 14, characterized in that said organic solvent is 1,4-dioxane or tetrahydrofurane and the said alkali hypohalite is sodium hypochlorite or sodium hypobromite.
17. The process of claim 1, characterized in that the hydrolysis in step (f) is carried out in an aqueous medium or in a mixture of water with a low molecular weight alcohol, at the reflux temperature of the alcohol and in the presence of an alkali hydroxide.
18. The process of claim 17, characterized in that the said alkali hydroxide is sodium or potassium hydroxide.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ES8801824 | 1988-06-13 | ||
| ES8801824A ES2006977A6 (en) | 1988-06-13 | 1988-06-13 | Ciprofloxacine bactericide prepn. |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1340561C true CA1340561C (en) | 1999-05-25 |
Family
ID=8256776
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000602049A Expired - Fee Related CA1340561C (en) | 1988-06-13 | 1989-06-07 | Process for preparing ciprofloxacine |
Country Status (5)
| Country | Link |
|---|---|
| KR (1) | KR920001134B1 (en) |
| CA (1) | CA1340561C (en) |
| ES (1) | ES2006977A6 (en) |
| GR (1) | GR1000405B (en) |
| PT (1) | PT90832B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5650533A (en) * | 1989-09-11 | 1997-07-22 | Rhone-Poulenc Agriculture Ltd. | Intermediates to herbicidal 4-substituted isoxazoles |
| ES2036941B1 (en) * | 1991-11-07 | 1994-01-16 | Inke Sa | PROCEDURE FOR THE OBTAINING OF ACID 1- (2,4-DIFLUOROFENIL) -6-FLUORO-7- (3-METHYL-1-PIPERACINIL) -4-OXO-1,4-DIHIDROQUINOLIN-3-CARBOXILICO AND ITS SALTS. |
| KR100437600B1 (en) * | 1999-08-17 | 2004-06-26 | 엘지전자 주식회사 | Conversion Service Board And Merthod For Charactor Information In Value Added Communication System |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3248505A1 (en) * | 1982-12-29 | 1984-07-05 | Bayer Ag, 5090 Leverkusen | 1-CYCLOPROPYL-6-FLUOR-1,4-DIHYDRO-4-OXO-7 (4- (OXOALKYL) -1-PIPERAZINYL / -3-QUINOLINE CARBONIC ACIDS AND THEIR DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF, AND THEIR CONTAINERS |
-
1988
- 1988-06-13 ES ES8801824A patent/ES2006977A6/en not_active Expired
-
1989
- 1989-05-25 GR GR890100344A patent/GR1000405B/en not_active IP Right Cessation
- 1989-06-07 CA CA000602049A patent/CA1340561C/en not_active Expired - Fee Related
- 1989-06-12 PT PT90832A patent/PT90832B/en not_active IP Right Cessation
- 1989-06-13 KR KR1019890008089A patent/KR920001134B1/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| KR910000701A (en) | 1991-01-30 |
| KR920001134B1 (en) | 1992-02-06 |
| PT90832B (en) | 1994-12-30 |
| GR1000405B (en) | 1992-06-30 |
| ES2006977A6 (en) | 1989-05-16 |
| GR890100344A (en) | 1990-05-11 |
| PT90832A (en) | 1989-12-29 |
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