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DK166411B1 - METHOD OF PREPARING 2,4-DICHLOR-5-FLUORO-BENZOIC ACID - Google Patents

METHOD OF PREPARING 2,4-DICHLOR-5-FLUORO-BENZOIC ACID Download PDF

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DK166411B1
DK166411B1 DK436685A DK436685A DK166411B1 DK 166411 B1 DK166411 B1 DK 166411B1 DK 436685 A DK436685 A DK 436685A DK 436685 A DK436685 A DK 436685A DK 166411 B1 DK166411 B1 DK 166411B1
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fluoro
dichloro
benzoic acid
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DK436685A (en
DK436685D0 (en
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Fritz Maurer
Klaus Grohe
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Bayer Ag
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C63/00Compounds having carboxyl groups bound to a carbon atoms of six-membered aromatic rings
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/45Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
    • C07C45/46Friedel-Crafts reactions
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/16Preparation of carboxylic acids or their salts, halides or anhydrides by oxidation
    • C07C51/29Preparation of carboxylic acids or their salts, halides or anhydrides by oxidation with halogen-containing compounds which may be formed in situ

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Description

i DK 166411 B1 oin DK 166411 B1 o

Den foreliggende opfindelse angår en særlig fremgangsmåde til fremstilling af 2,4-dichlor-5-fluor-benzoe-syre, et mellemprodukt til fremstillingen af antibakteriel-le midler.The present invention relates to a particular process for the preparation of 2,4-dichloro-5-fluoro-benzoic acid, an intermediate for the preparation of antibacterial agents.

5 Det er allerede kendt, at trihalogenbenzoesyrer.5 It is already known that trihalobenzoic acids.

kan fremstilles ved forsæbning af trihalogen-trihalogen-methyl-benzen. Således dannes der ved forsæbningen af 2,4--dichlor-5-fluor-trichlormethylbenzen 2,4-dichlor-5-fluor--benzoesyre, jvf. EP nr. 78.362.can be prepared by saponification of trihalo-trihalo-methyl-benzene. Thus, by the saponification of 2,4 - dichloro-5-fluoro-trichloromethylbenzene, 2,4-dichloro-5-fluoro - benzoic acid is formed, cf. EP No. 78,362.

10 Endvidere er det kendt, at acyleringen med alipha- tiske carboxylsyrehalogenider ved dihalogenbenzener er særdeles vanskelig og ikke skal finde sted ved trihalogenben-zener, jvf. Methoden der organischen Chemie (Houben-Weyl-Miil-ler) bind 7/2a, 43 (1973), Thieme-Verlag, Stuttgart.Furthermore, it is known that the acylation with aliphatic carboxylic acid halides by dihalogenbenzenes is extremely difficult and should not take place in trihalogenbenzenes, cf. the method of Organic Chemie (Houben-Weyl-Miiller) Volume 7/2a, 43 ( 1973), Thieme-Verlag, Stuttgart.

15 Desuden er det kendt, at man ved acyleringen med carboxylsyreanhydrider, såsom eddikesyreanhydrid, ud fra 2.4- dichlorfluorbenzen, i nærværelse af aluminiumtrichlo-rid, får 2,4-dichlor-5-fluor-acetophenon i dårligt udbytte, jvf. CA 58, 11243 g.In addition, it is known that in the acylation with carboxylic anhydrides, such as acetic anhydride, from 2,4-dichlorofluorobenzene, in the presence of aluminum trichloride, 2,4-dichloro-5-fluoroacetophenone is obtained in poor yield, cf. CA 58, 11243 g.

20 Overraskende har det nu vist sig, at man får 2,4- -dichlor-5-fluorbenzoesyre med formlenSurprisingly, it has now been found that 2,4- dichloro-5-fluorobenzoic acid of the formula

Cl-//\\-C00HCl - // \\ - C00H

r 25 i særdeles godt udbytte og høj renhed ved, at man omsætter 2.4- dichlor-fluorbenzen med acetylchlorid, i nærværelse af acyleringskatalysatorer og eventuelt i nærværelse af fortyndingsmidler, ved temperaturer mellem 10°C og 150°C, og omsætter det på denne måde dannede reaktionsprodukt 30 2,4-dichlor-5-fluor-acetophenon med formlenr 25 in very good yield and high purity by reacting 2.4-dichlorofluorobenzene with acetyl chloride, in the presence of acylation catalysts and optionally in the presence of diluents, at temperatures between 10 ° C and 150 ° C, and reacting in this way reaction product formed 2,4-dichloro-5-fluoroacetophenone of the formula

Cl-Ø-CQ-CH, (II) 35 eventuelt efter isolering, med en natriumhypochloritopløs-ning (i form af den såkaldte chlorlud), ved en temperatur mellem 0°C og 140°C.Optionally after isolation, with a sodium hypochlorite solution (in the form of the so-called chlorine liquor), at a temperature between 0 ° C and 140 ° C.

OISLAND

DK 166411 B1 2DK 166411 B1 2

Det lykkes overraskende, ved hjælp af fremgangsmåden ifølge opfindelsen, at udføre en acylering af 2,4-dichlor--fluorbenzen med et carboxylsyrechlorid i meta-stilling til det mere elektronegative halogen med højt udbytte og 5 selektivitet. Dette er så meget mere overraskende, da man ifølge teknikkens stade ved acyleringen af halogenbenzener måtte have forventet en acylering i ortho- eller para-stil-ling af det mere elektronegative halogen, jvf. Methoden der organischen Chemie (Houben-Weyl-Miiller) bind 7/2a 43 (1973) , 10 Thieme-Verlag, Stuttgart.Surprisingly, by the process of the invention, we succeed in performing an acylation of 2,4-dichlorofluorobenzene with a carboxylic acid chloride in meta position to the more electronegative halogen with high yield and selectivity. This is all the more surprising, since according to the state of the art, when acylating halogen benzenes, one would have expected an acylation in the ortho or para position of the more electronegative halogen, cf. the method of the Organic Chemie (Houben-Weyl-Miiller) 7 / 2a 43 (1973), 10 Thieme-Verlag, Stuttgart.

De ovennævnte kendte fremgangsmåder har en række ulemper. Således fremstilles der ved fremstillingen af 2,4-dichlor-5-fluor-trichlormethylbenzen som mellemprodukt en triazen, som kun vanskeligt lader sig håndtere på grund 15 af sine ugunstige fysiologiske egenskaber.The above known methods have a number of disadvantages. Thus, in the preparation of 2,4-dichloro-5-fluoro-trichloromethylbenzene, an intermediate is produced a triazene which is difficult to handle only because of its unfavorable physiological properties.

Endvidere er flere trin nødvendige ved denne fremgangsmåde til fremstillingen af 2,4-dichlor-5-fluor-benzoe-syre.Furthermore, several steps are required in this process for the preparation of 2,4-dichloro-5-fluoro-benzoic acid.

Ved den i litteraturen beskrevne acylering af 2,4-20 -dichlor-5-fluorbenzen i nærværelse af eddikesyreanhydrid er udbyttet af reaktionsprodukt særdeles ringe.In the acylation of 2,4-20-dichloro-5-fluorobenzene described in the literature in the presence of acetic anhydride, the yield of reaction product is extremely poor.

Anvender man 2,4-dichlor-fluorbenzen og acetyl-chlorid som udgangsstoffer, aluminiumchlorid som katalysator og chlorlud, kan reaktionsforløbet gengives således 25 ved det følgende reaktionsskema:If 2,4-dichlorofluorobenzene and acetyl chloride are used as starting materials, aluminum chloride as catalyst and chlorine liquor, the course of the reaction can thus be represented by the following reaction scheme:

Cl -Cl ♦ CHj-CO-Cl A1Cls— > Cl-^^-CO-CHj 30 - —Cl -Cl ♦ CH2-CO-Cl A1Cls—> Cl - ^^ - CO-CHj 30 - -

Chlorlud-> Cl-^^COOHChlorlud-> Cl - ^^ COOH

2,4-Dichlor-fluorbenzen er en kendt forbindelse i 35 den organiske kemi.2,4-Dichlorofluorobenzene is a known compound in organic chemistry.

OISLAND

DK 166411 B1 3DK 166411 B1 3

Reaktionstemperaturen kan varieres inden for et større område. Man arbejder ved acyleringen almindeligvis således ved temperaturer mellem 10°C og lSO^C, fortrinsvis mellem 20°C og 130°C, især mellem 80°C og 130°C. Den føl-5 gende oxidation med den såkaldte chlorlud gennemføres almindeligvis ved temperaturer mellem 0°C og 140°C, fortrinsvis mellem 20°C og 120°C. Reaktionen gennemføres almindeligvis ved normalt tryk.The reaction temperature can be varied within a larger range. Thus, the acylation is generally employed at temperatures between 10 ° C and 10 ° C, preferably between 20 ° C and 130 ° C, especially between 80 ° C and 130 ° C. The subsequent oxidation with the so-called chlorine liquor is generally carried out at temperatures between 0 ° C and 140 ° C, preferably between 20 ° C and 120 ° C. The reaction is usually carried out under normal pressure.

Fremgangsmåden ifølge opfindelsen gennemføres for-10 trinsvis uden fortyndingsmidler.The process of the invention is preferably carried out without diluents.

Som katalysator kommer på tale til fremgangsmåden ifølge opfindelsen acyleringskatalysatorer, såsom jern-III--chlorid/ zinkchlorid eller alminiumchlorid, fortrinsvis alminiumchlorid.As the catalyst, the process of the invention is acylation catalysts such as ferric III chloride / zinc chloride or alminium chloride, preferably alminium chloride.

15 Som oxidationsmiddel kommer i betragtning til frem gangsmåden ifølge opfindelsen den såkaldte chlorlud, en na-triumhypochlorit-opløsning i vand.As the oxidizing agent, the so-called chlorine liquor, a sodium hypochlorite solution in water, is considered in the present invention.

Ved gennemføringen af fremgangsmåden ifølge opfindelsen anvender man almindeligvis pr. mol 2,4-dichlor-fluor-20 benzen fra 1 til 3 mol acetylchlorid og fra 1 til 3 mol al-uminiumchlorid. Efter at reaktionen er tilendebragt, sættes reaktionsblandingen til is og tages op i et med vand ikke--blandbart fortyndingsmiddel, såsom methylenchlorid eller chloroform. Reaktionsproduktet kan imidlertid også skilles 25 fra uden anvendelse af fortyndingsmidler. Eventuelt efter fjerhelse af ekstraktionsmidlet oxideres remanensen i nærværelse af fra 2 til 4 liter, fortrinsvis fra 2,1 til 3,3 liter chlorlud (150 g aktivt chlor pr. liter) pr. mol udgangsprodukt. Derpå fældes 2,4-dichlor-5-fluor-benzoesyren 30 ud med en mineralsyre, såsom saltsyre, og skilles derpå fra ved sugning.In carrying out the method according to the invention, one is usually used per moles of 2,4-dichlorofluorobenzene from 1 to 3 moles of acetyl chloride and from 1 to 3 moles of aluminum chloride. After the reaction is complete, the reaction mixture is added to ice and taken up in a water immiscible diluent such as methylene chloride or chloroform. However, the reaction product can also be separated without the use of diluents. Optionally after removal of the extractant, the residue is oxidized in the presence of from 2 to 4 liters, preferably from 2.1 to 3.3 liters of chlorine liquor (150 g of active chlorine per liter) per liter. moles of starting product. The 2,4-dichloro-5-fluoro-benzoic acid 30 is then precipitated with a mineral acid such as hydrochloric acid and then separated by suction.

Den ved fremgangsmåden ifølge opfindelsen let tilgængelige 2,4-dichlor-5-fluor-benzoesyre lader sig eksempelvis anvende til syntese af antibakterielle midler. Man 35 kan således ud fra denne syre fremstille de substituerede oxoquinolincarboxylsyrer, forbindelser med højt baktericid potens, ifølge følgende ligninger, jvf. eksempelvis EP nr. 78.362: DK 166411 B1 4 oThe 2,4-dichloro-5-fluoro-benzoic acid readily available in the process of the invention can be used, for example, for the synthesis of antibacterial agents. Thus, from this acid, the substituted oxoquinoline carboxylic acids, compounds of high bactericidal potency, can be prepared according to the following equations, cf., for example, EP No. 78.362: DK 166411 B1 4 o

Cl^COOH SOCI2—> C1^C0CI CH?(C00C2H5)2—> f3—f F' 5 /-rcl . /-^1Cl 2 COOH SOCl 2 -> C 1 C0Cl CH 2 (C00 C 2 H 5) 2 -> f 3 - f F '5 / -rcl. / - ^ 1

Cl -y'^V-CO-CH( COOC2H5 )2 --> Ciy/_\\-C0-CH2-C00C2H5 p3—' F3—' OC2H5 HCtOCiiHfiJa > ci-^ioi-cooc2H5 > HN-O 0Cl -y '^ V-CO-CH (COOC2H5) 2 -> Ciy / _ \\ - C0-CH2-C00C2H5 p3—' F3— 'OC2H5 HCtOCiiHfiJa> ci- ^ ioi-cooc2H5> HN-O 0

Cl CH J.CDOC2H5 ci-^^-cd-i!-cooc2H5 ^Β£ί—> i^T 1 -> k 20 0 oCl CH J.CDOC2H5 ci - ^^ - cd-i! -Cooc2H5 ^ Β £ ί—> i ^ T 1 -> k 20 0 o

RN NH F -^XnOOHRN NH F - ^ XnOOH

~\,&0~ \, & 0

1 RN N J1 RN N J

Å w Å 25 R = H, Alkyl FremstillingseksempelÅ w Å 25 R = H, Alkyl Preparation Example

C1-/^V)-C00HC 1 - / V ^) -C00H

30 F'- ^30 F'- ^

Til en blanding af 33 g (0,2 mol) 2,4-dichlor-fluor-benzen og 66,8 g (0,5 mol) aluminiumchlorid ved fra 20°C til 40°C sættes der 23,6 g (0,3 mol) acetyichlorid, og der omrøres derpå i 2 timer ved 120°C. Den endnu varme blanding sættes 35 til 250 g is, og den olie, som udskiller sig, tages op i methylenclorid. Opløsningsmidlet bortdampes, og der sættes 450 ml chlorlud (150 g aktivt chlor pr. liter) til remanen- 5 DK 1 6ό4ί Ί ΒΊ Ο sen og omrøres først i 1 time uden opvarmning og koges derpå i 2 timer ved tilbagesvaling. Efter fraskillelse af den dannede chloroform tilsætter man 300 ml vand, der tilsættes 10 ml 40%'s natriumhydrogensulfit-opløsning og derpå 5 koncentreret saltsyre, indtil man opnår en pH-værdi på 1.To a mixture of 33 g (0.2 mole) of 2,4-dichlorofluorobenzene and 66.8 g (0.5 mole) of aluminum chloride at from 20 ° C to 40 ° C is added 23.6 g (0 (3 moles) of acetylchloride and then stirred for 2 hours at 120 ° C. The still hot mixture is added 35 to 250 g of ice and the oil separating is taken up in methylene chloride. The solvent is evaporated and 450 ml of chlorine liquor (150 g of active chlorine per liter) is added to the residue and first stirred for 1 hour without heating and then boiled for 2 hours at reflux. After separation of the chloroform formed, 300 ml of water is added, 10 ml of 40% sodium hydrogen sulfite solution and then 5 concentrated hydrochloric acid are added until a pH of 1 is reached.

Man får på denne måde 33,5 g (80% af teorien) 2,4--dichlor-5-flour-benzoesyre som farveløst pulver med et smeltepunkt på 139°C.This gives 33.5 g (80% of theory) of 2,4-dichloro-5-fluorobenzoic acid as a colorless powder, mp 139 ° C.

10 15 20 25 30 3510 15 20 25 30 35

Claims (5)

1. Fremgangsmåde til fremstilling af 2,4-dichlor--5-fluor-benzoesyre med formlen . r^1 Cl-i^VCOOH (I) kendetegnet ved, at man omsætter 2,4-dichlor--fluor-benzen med acetylchlorid, i nærværelse af acyle-10 ringskatalysatorer og eventuelt i nærværelse af fortyndingsmidler/ ved temperaturer mellem 10°C og 150°C, og omsætter det på denne måde dannede reaktionsprodukt 2,4--dichlor-5-fluor-acetophenon med formlen 15 (II) eventuelt efter isolering, med en natriumhypochlorit-op-løsning, (i form af den såkaldte chlorlud) , ved en tempera-20 tur mellem 0°C og 140°C, og isolerer forbindelsen med formlen I ved gængse fremgangsmåder.A process for preparing 2,4-dichloro-5-fluoro-benzoic acid of the formula. r ^ 1 Cl-i ^ VCOOH (I) characterized by reacting 2,4-dichlorofluorobenzene with acetyl chloride, in the presence of acylation catalysts and optionally in the presence of diluents / at temperatures between 10 ° C and 150 ° C, reacting the reaction product thus formed 2,4 - dichloro-5-fluoroacetophenone of formula 15 (II), optionally after isolation, with a sodium hypochlorite solution, (in the form of the so-called chlorine liquor). ), at a temperature between 0 ° C and 140 ° C, and isolates the compound of formula I by conventional methods. 2. Fremgangsmåde ifølge krav 1, kendetegnet ved, at man anvender aluminiumtrichlorid som acy-leringskatalysator.Process according to claim 1, characterized in that aluminum trichloride is used as an acylation catalyst. 3. Fremgangsmåde ifølge kravene 1 og 2, kende tegnet ved, at man udfører omsætningen med acetyl-chlorid ved temperaturer mellem 20°C og 130°C.Process according to claims 1 and 2, characterized in that the reaction is carried out with acetyl chloride at temperatures between 20 ° C and 130 ° C. 4. Fremgangsmåde ifølge kravene 1 og 2, kendetegnet ved, at man gennemfører omsætningen med na- 30 triumhypochlorit-opløsningen (chlorlud) ved temperaturer mellem 20°C og 120°C.Process according to claims 1 and 2, characterized in that the reaction is carried out with the sodium hypochlorite solution (chlorine liquor) at temperatures between 20 ° C and 120 ° C. 5. Fremgangsmåde ifølge kravene 1 til 4, kendetegnet ved, at det i forløbet af fremgangsmåden dannede 2,4-dichlor-5-fluor-acetophenon uden isolering om- 35 sættes med natriumhypochlorit-opløsningen (chlorlud).Process according to claims 1 to 4, characterized in that the 2,4-dichloro-5-fluoro-acetophenone formed during the course of the process is reacted without isolation with the sodium hypochlorite solution (chlorine liquor).
DK436685A 1984-09-27 1985-09-26 METHOD OF PREPARING 2,4-DICHLOR-5-FLUORO-BENZOIC ACID DK166411B1 (en)

Applications Claiming Priority (2)

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DE19843435392 DE3435392A1 (en) 1984-09-27 1984-09-27 METHOD FOR THE PRODUCTION OF 2,4-DICHLOR-5-FLUOR-BENZOESAEEURE
DE3435392 1984-09-27

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DK436685D0 DK436685D0 (en) 1985-09-26
DK436685A DK436685A (en) 1986-03-28
DK166411B1 true DK166411B1 (en) 1993-05-17

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EP (1) EP0176026B1 (en)
JP (1) JPH0647568B2 (en)
KR (1) KR910008936B1 (en)
AU (1) AU569176B2 (en)
CA (1) CA1255330A (en)
DD (1) DD239591A5 (en)
DE (2) DE3435392A1 (en)
DK (1) DK166411B1 (en)
ES (1) ES8605462A1 (en)
FI (1) FI86413C (en)
GR (1) GR852346B (en)
HU (1) HU193345B (en)
IE (1) IE72493B1 (en)
IL (1) IL76466A (en)
NO (1) NO159080C (en)
NZ (1) NZ213599A (en)
PH (1) PH24252A (en)
PT (1) PT81144B (en)
SU (1) SU1470175A3 (en)
UA (1) UA8020A1 (en)
ZA (1) ZA857432B (en)

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US4791225A (en) * 1986-01-20 1988-12-13 Kyorin Pharmaceutical Co., Ltd. Halogenobenzoic acid derivatives and their preparation
DE3641099A1 (en) * 1986-12-02 1988-06-09 Hoechst Ag METHOD FOR PRODUCING 4- (2'-CHLORETHYL) BENZOESIC ACID
DE3840371A1 (en) * 1988-11-30 1990-05-31 Lentia Gmbh Process for the preparation of 2,4,5-trifluorobenzoic acid
US4996355A (en) * 1989-04-14 1991-02-26 Mallinckrodt, Inc. Novel intermediates for the production of 2,4,5-trifluorobenzoyl fluoride
DE3925036A1 (en) * 1989-07-28 1991-01-31 Riedel De Haen Ag METHOD FOR PRODUCING FLUORINATED BENZOESAURS
GB9107684D0 (en) * 1991-04-11 1991-05-29 Berge Richard Panel system
DE19617558A1 (en) * 1996-05-02 1997-11-06 Hoechst Ag Process for the preparation of 4,5-dichloro-2-methylbenzoic acid
DE19733243A1 (en) 1997-08-01 1999-02-04 Bayer Ag Process for the preparation of 3-cyano-2,4-dihalogen-5-fluoro-benzoic acid
RU2155185C1 (en) * 1999-03-24 2000-08-27 Новосибирский институт органической химии им. Н.Н. Ворожцова СО РАН Method of preparing partially fluorinated benzoic acids

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DE2412855C2 (en) * 1974-03-18 1983-03-31 Basf Ag, 6700 Ludwigshafen Process for the production of carboxylic acids
DE3035355A1 (en) * 1980-09-19 1982-04-29 Bayer Ag, 5090 Leverkusen METHOD FOR PRODUCING 3-BROMO-4-FLUORO-BENZOESIC ACID
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
DE3248506A1 (en) * 1982-12-29 1984-07-05 Bayer Ag, 5090 Leverkusen 1-CYCLOPROPYL-6-FLUOR-1,4-DIHYDRO-4-OXO-7 (ALKYL-1-PIPERAZINYL) -3-CHINOLINE CARBONIC ACIDS, METHOD FOR THE PRODUCTION THEREOF AND THEIR CONTAINING ANTIBACTERIAL AGENTS

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KR910008936B1 (en) 1991-10-26
EP0176026B1 (en) 1987-11-25
IE72493B1 (en) 1997-04-23
GR852346B (en) 1986-01-27
JPH0647568B2 (en) 1994-06-22
DE3561054D1 (en) 1988-01-07
PH24252A (en) 1990-05-04
CA1255330A (en) 1989-06-06
ZA857432B (en) 1986-05-28
ES8605462A1 (en) 1986-03-16
KR860002446A (en) 1986-04-26
UA8020A1 (en) 1995-12-26
NO853605L (en) 1986-04-01
DE3435392A1 (en) 1986-04-03
JPS6185350A (en) 1986-04-30
PT81144A (en) 1985-10-01
FI853686L (en) 1986-03-28
EP0176026A1 (en) 1986-04-02
PT81144B (en) 1988-01-22
IE852380L (en) 1986-03-27
IL76466A (en) 1988-12-30
DK436685A (en) 1986-03-28
FI86413B (en) 1992-05-15
IL76466A0 (en) 1986-01-31
NZ213599A (en) 1988-01-08
FI86413C (en) 1992-08-25
SU1470175A3 (en) 1989-03-30
AU4792485A (en) 1986-04-10
AU569176B2 (en) 1988-01-21
NO159080B (en) 1988-08-22
ES547345A0 (en) 1986-03-16
NO159080C (en) 1988-11-30
DD239591A5 (en) 1986-10-01
DK436685D0 (en) 1985-09-26
FI853686A0 (en) 1985-09-25
HUT39410A (en) 1986-09-29
HU193345B (en) 1987-09-28

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