CA1044239A - 6-alkoxy-7-hydroxyquinoline-3-carboxylic acids and derivatives thereof - Google Patents
6-alkoxy-7-hydroxyquinoline-3-carboxylic acids and derivatives thereofInfo
- Publication number
- CA1044239A CA1044239A CA207,894A CA207894A CA1044239A CA 1044239 A CA1044239 A CA 1044239A CA 207894 A CA207894 A CA 207894A CA 1044239 A CA1044239 A CA 1044239A
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- group
- compound
- process according
- formula
- general formula
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
- C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
Abstract
ABSTRACT
This invention relates to a process for the preparation of the com-pounds of the general formula I:
(I) wherein R1 stands for lower alkyl group, R2 stands for a lower alkyl group or an aralkyl group, R3 stands for hydrogen or a lower acyl group which comprises (a) reducing a compound of the general formula II:
(II) wherein R1 and R3 are defined above, to a compound of the general formula III:
(III) and reacting the compound thus obtained with an ethoxy-methylene-malonic acid-diester of the general formula IV:
(IV) wherein R2 is defined above and subjecting the compound of the general formula V:
(V) thus obtained, wherein R1, R2 and R3 are defined above, to ring-closure; or (b) reacting a compound of the general formula:
(VI) wherein R1 and R3 are defined above, with ortho-formic acid ester and alkyl-malonate and subjecting the compound of the general formula V thus obtained, wherein R1, R2 and R3 are defined above, to ring-closure; or (c) subjecting a compound of the general formula I, wherein R1 and R2 are defined above and R3 stands for a lower acyl group, to a selective acyl-cleaving; or (d) reacting the compound of the general formula III, wherein R1 is defined above and R3 stands for hydrogen, with ethyl-.alpha.-cyano-.beta.-ethoxy-acrylate and subjecting the compound of the general formula VII:
(VII) thus obtained, wherein R1 is defined above, to ring-closure and subjecting the new compound of the general formula VIII:
This invention relates to a process for the preparation of the com-pounds of the general formula I:
(I) wherein R1 stands for lower alkyl group, R2 stands for a lower alkyl group or an aralkyl group, R3 stands for hydrogen or a lower acyl group which comprises (a) reducing a compound of the general formula II:
(II) wherein R1 and R3 are defined above, to a compound of the general formula III:
(III) and reacting the compound thus obtained with an ethoxy-methylene-malonic acid-diester of the general formula IV:
(IV) wherein R2 is defined above and subjecting the compound of the general formula V:
(V) thus obtained, wherein R1, R2 and R3 are defined above, to ring-closure; or (b) reacting a compound of the general formula:
(VI) wherein R1 and R3 are defined above, with ortho-formic acid ester and alkyl-malonate and subjecting the compound of the general formula V thus obtained, wherein R1, R2 and R3 are defined above, to ring-closure; or (c) subjecting a compound of the general formula I, wherein R1 and R2 are defined above and R3 stands for a lower acyl group, to a selective acyl-cleaving; or (d) reacting the compound of the general formula III, wherein R1 is defined above and R3 stands for hydrogen, with ethyl-.alpha.-cyano-.beta.-ethoxy-acrylate and subjecting the compound of the general formula VII:
(VII) thus obtained, wherein R1 is defined above, to ring-closure and subjecting the new compound of the general formula VIII:
Description
The present invention is directed to the preparation of new compounds of the gener~l formula I, which are useful intermediates in the synthesis of the known coccidiostatic:6,7-dialkoxy~quinoline-carboxylic acid ester, to the new compounds per se and to coccidiostatic compositions containing the new compounds as active~ ingredient.
Thus~ ~his invention relates to compounds of the general formula I
or Ia ~30 ~ ~ P ~30 ~ ~
R10 (Ia) R10 H (I) or a pharmaceutically acceptable acid addition or base salt thereof, ~herein R represents an alkyl group of 1 to 4 carbon atoms~ R3 represents hydrogen or an alkanoyl group of 2 to 4 carbon atoms and R4 represents -CN, -COOH
or the group -COOR ~ wherein R represents a benzyl group or an alkyl group of 1 to 4 carbon atoms.
The compounds of this invention may exist in tautomeric keto and enol forms as represented by formula (I) and (Ia).
There are several methods described for the preparation of the 6,7-dialkoxy-quinoline-carboxylic acid esters. The common feature of these methods in that as starting material 6~7-dialkoxy-derivatives are used.
~ccording to Dutch Patent Specifications Nos. 6,508,117 and $,600,447 and British Patent Specification No. 1~172~841 the 6,7-dialkoxy-4-oxy-quinoline is prepared from a 6,7-dialkoxy-4-acyloxyrquinoline-derivative.
According to an other method the 6,7-dialkoxy-4-oxy-quinolines are prepared by thermal ring-closure, where the compounds are contaminated at a high temperature with such decomposed substances which can be hardly removed. The purification of such products is very difficult as this kind ~ , B
. . . ~ . . .
~ ,.f~4~ 3~
of product is not soluble~ thus the recrystallization is greatly obstructed.
These disadv~ntages may be eliminated by the present invention.
The 6-acyloxy-derivatives according to the present invention may unexpected-ly be prepared with a very good yield by the thermal ring-closure and may be easily purified and converted into pure 6-hydro~y-quinoline-derivative~ which is suitable for further reaction.
In French Patent Specification No. 1,531,495 6-alkoxy-7-acyloxy-4-oxy~quinoline-3~carboxylic acid derivatives are described, which compounds may be considered as structural isomers of one of the compounds of the -present invention.
In French Patent Specification No 2,013~519 such 6-hydroxy-quinoline-derivatives are described, wherein a cycloalkyl group is attached to the 7-8 position of the quinoline ring.
The new 6-acyloxy and 6-hydroxy compounds of the present inYention show coccidiostatic activity themselves.
The 6-acetoxy-7-ethox~- 4Oxy-quinoline-3-carboxylic acid-ethyl-ester shows 48% activity compared to 6 n-decyloxy-7-ethoxy-4-hydroxy-3-carbethoxy-quinoline ¦A) but shows approximately the same activity as 1~2-propyl-5-amino-5-pyrimidyl-methyl-~2-methyl-pyridinium7-chloride (B) which can be regarded as a standard from the therapeutical point of view.
The 6-hydroxy-7-ethoxy-4-oxy-quinoline-3-carboxylic acid-ethyl-ester shows 54% activity, when compared with (A) and shows also about the same activity as (B).
According to one feature of the present invention, B
3~
there is provided a process for the preparation of a compound of the general formulal (I)'or (Ia)'.
OH
R30 ~ -c--~
R O (Ia) R O
or a pharmaceutically acceptable acid addition or base salt thereof, wherein R reparesents an alkyl group of 1 ~o 4 carbon atoms~ R3 represents hydrogen or an alkanoyl group of 2 to 4 carbon atoms, and R4 represents -CN, -COOH or the group -COOR , wherein R2 reprcsents a ben7yl group or an alkyl group of 1 to 4 carbon atoms; which comprises (a) subjecting a compound of the formu~a:
1 ~\ COOR2 .
R O NH-CH=C (Va) X ., wherein X is the group -CN or -COOR and wherein R , R and R3 are as de~
f - a/
fined above;~and where step (a) can be followed by the additional step of ~ ~
(b) hydrolyzing a compound of formula (I) or (Ia)oobtained in which R4 is ~: ;
: -CN or a group -COOR as hereinbefore defined to produce the corresponding compound of formula (I) or (Ia) in which R4 is the -COOH group; and where step (a) or (b) can be followed by the additional step of (~) hydrolyzing a compound of formula (I~ or (Ia~ in which R3 is an alkanoyl group to produce a corresponding compound of formula (I~ or (Ia~ in which R3 is a hydrogen ;
atom; and where step (a), (b) or (c) can be followed by the additional step ~ .
of (d) converting a base or acid of formula ~I) or (Ia~ obtained into a D -4- ::
~)4~3~ :
corresponding pharmaceutically acceptable salt by reaction with an acid or a base respectively.
As indicated above in the ~eneral formulae I and Ia R stands for a straight or branched chained alkyl group contairling 1-4 carbon atoms and is preferably an ethyl group.
Similarly, R stands for a straight or branched chained alkyl group con-taining 1-4 carbon atoms and is preferably an ethyl group as it represents a benzyl group.
R3 stands for a hydrogen atom or an alkanoyl group of 2 to 4 10carbon atoms~ which is preferably an acetoxy group.
According to an embodiment of this invention, the starting materials of formula (Va) are prepared by reacting an aniline derivative of the formula ~ (III) 1~ ' ' .
wherein R and R3 are as defined aabove~ with an ethoxymethylenemalonic acid derivative of the formula: '~
cooR2 C2H50 - CH = I (IVa) ;
.
wherein R and X are as defined above.
The compounds of formula (III) are conveniently prepared by the reduction of a corresponding nitro compound of the formula:
R 0 ~ (II) R 0 2 '~
~ a $-S- ~
~o~
wherein R and R3 are as defined above.
The compounds of the gencral formula Il~ wherein R3 stands for hydrogen are prepared according to D.F. Page and 0. Clinton: Org. Chem. 27, 218, 1962. Compounds of the general formula II~ wherein R3 stands for an alkanoyl group are prepared by alkanoylation of the hydroxy compounds.
The reduction of the compounds of the general formula II is preferably carried out by hydrogenation in the presence of a catalyst~
preferably in the presence of palladium on carbon catalyst at atmospheric pressure or under pressure.
When reducing the alkanoyl-derivatives~ the reaction is carried out in a solvent, preferably in ethyl acetateO
The reduction of the phenol of the general formula II is carried out preferably in a mixture of hydrochloric acid-water or hydrochloric acid-water-acetic acid as solvent.
The condensation of the compound of the general formula III with the compound of the general formula IVa is carried out preferably in a solvent~ particularly by boiling~e~hyl,~a¢etate~
The condensation of the hydroxy-compound of the general formula III
with the compound of the general formula IVa is also carried out in a sol-vent~ preferably in benzine under heating~ though the benzine is present rather as a diluting agent. The reaction is carried out also in the melt.
When melting the hydroxy-compound of the general formula III with the malonic acid-derivative without any solventg '' :.
~ .
B` -5a-the compound of the general formula Va need not to be isolated~ but the reaction mi~ture can be directly subjected to ring-closure in diphyl a*
250C.
According to another embodiment of the present invention the ring-c]osure of the compound of the general formula Va wherein R3 stands for hydrogen is carried out in sulphuric acid-acetic acid anhydride~ by dissolving the condensed compound in acetic acid anhydride and by adding the sulphuric acid dropwise to the solution. The temperature ~ the mixture will rise to 60 C during the addition of the sulphuric acid and the mixture will be stirred for an other 10 minutes. The product precipitates when pouring it in water.
The compounds of the general formula I, wherein R3 stands for hydrogen~ i.e. compownds of the formula IA
'''~.' "
~ :
3~
OH o HO ~ COOR HO ~ COOR
I I ~
1 ~ 1 ~ N ~ (IA) H
may also be prepared by the following methods:
A particularly pure product may be obtained~ when subjecting the compounds of the general formula I, wherein R3 stands for acyl group to selective acyl-splitting.
The acyl-splitting is carried out in a mild alkaline medium ~-preferably in the presence of potassium hydrogen carbonate in a mixture of water and alcohol at the boiling-point of the mixture. Under s~ch circum-stances the ester group remains uneffected.
According to a particular embodiment of the process of the present invention described in general terms above, the 6-hydroxy-compounds are prepared by reacting compounds of the general formulà III, wherein R stands ~-for hydrogen with ethyl-~cyano-~-ethoxy-acrylate and subjecting the com-po~md of the general formula VII
::
J~l~ ICOOC2H5 (VII) -:
R O NH-CH=C
wherein R is defined above, thus obtained to ring-closure . :
A new compound of the general formula VIII
' ' ' : , ' ' ,'"
7 .
B ~
.
3~3 0~1 0 H0 CN ~0 ~ ~ CN (VIII) R O R O
wherein R is defined above can be subjected ~o asidic or alkalin0 hydrolysis which is optionally followed by este~ification~ or the nitrile of the general formula VIII can be directly reacted with alcohol in an acidic medium.
The compounds of the general formula I, wherein R3 stands for hydrogen can be hydrolysed to thc corresponding acid. The acid obtained can be converted to another ester by reaction with the correspond~ng alcohol A base of formula Ia or I obtained can be converted to a salt, or set free from the salts thereof. The esters form salts~ for example a hydrochloride or hydrobromide salt.
The compounds of the general formula I may be a~mixed with the usual pharmaceutically acceptable carriers and used as a coccidiostatic agent.
The said coccidiostatic compositions may be finished in solid (e.g. tablets~ pills~ capsules~ granules) or liquid (e.g. solutions, emul-sions~ suspensions~ form. The compositions may be prepared by conventional method known per se and may contain the usual carriers or diluents and~ if `
necessary additives.
Further details of our invention are to be found in the Examples~
without limiting the scope of our invention to the Examples.
xample 22.5~ g (0.1 mole~ of 4-acetoxy-3-ethoxy-nitro-benzene are hydro-genated in 22.5 ml of ethyl acetate in the presence of 5 g of palladium on ;
charcoal catalyst at 5-lO atm. After the consumption of hydro~en in the desired amount, the catalyst is filtered and the reaction mixture is ! 30 evaporated to dry. On cooling crystalline 4-acetoxy-3-ethoxy-aniline is ob-tained, which is wa~hed with cold alcohol. Yield 86%, mp.: 9~ C.
Analysis:
Calculated: C 61~3 % H 6~71 % N 7017 %
~ound: C 61.30 % H 6~40 % N 6.81 %~
xample 2 25~4 g (0.1~ moles) o~ 4-ace-toxy-3-ethoxy-anlline ~re dissolved in 250 ml of ethyl acetate and 32~4 ~ ~0~15 moles) of ethoxy methylene-malonic acid diethyl-ester are added~
'~he reaction mixture is boiled for 3hours~ evaporated to dry and the residue is crystallized by cooling~ ~he substance is washed wi-th cold alcohol. ~hus white 4-acetoxy-3-ethoxy-anillno-methylene-malonic acid diethyl-ester i~
obtained with a yield of 91 %. Mp.: 102 C.
~nalysis:
Calculated; C 59~17 % H 6.34 % ~ 3.83 o/O
~ound: a 59 ~ ~ o/o H 6.50 % N 3~91 %.
1~ le 3 ~ 6~54 g (0.1 mole) o~ 4-acetox~-3-ethox~-anilino-methyle~e-malonic acid diethyl-ester are boiled in 365 ml o~ diphyl ~or 60 minutes. ~he product is successively precipitated from the reaction mixture. ~he ~uspension i~ cooled, diluted with 350 ml of petrol and filtered~
~he ~ub~tance o~ the filter is covered with pe-trol7 thus ; 25 b~ige 6-acetoxy-7-ethoxy-4-hydroxy-quinoline-~-carboxylic acid eth~l-ester is obtained. Yield 95 %9 mp.: ~00 C
(deoompo~ition). After recrystallization from dimethyl-sulfoxide the product melt~ at ~10 C~ -y9i9:
.
. .
:
~, 3~
Calculated C 6V,I8l% H 5.36 % N 4~38 %
~ound: a 60,20 '/0 H 5016 % N 4~32 %.
L~
The corresponding benzyl ester is obtained, when u~ing ethoxy-meth~len~-malo~ic acid-dibenzyl-ester instead o~
~thoxy-m~th~lene-malonic acid-dieth~l-ester. 4-acetox~-3-ethox~-aniline is reacted with ethoxy~methylene~malonic acid-dibenz~l-ester in eth~l acetate, whereafter the 6-acetoxy-7-ethoxy-4-ox~-quinoline-3 carbox~lic acid-benzyl-1Q ester is obtained without isolation of the compoundobtained a~ter evaporating the reaction mixture and after cyclisation in diphyl~ Mp.: 260 ~ (decomposition)~ ~he crude product is of beige colour~ ~fter recrystallization from dimethylformamide white cr~stalline substance is obtained. Mp.; 265 C (decomposition).
~:~al;ysis O ' .
aalculated: a 66.14 % H 5.02 % ~ ~.67 % .~
~ou~ds C 65~80 % H 5~27 % ~ 3.78 %- ;
~xample 5 2018.~1 g (0~1 mole) of 2-ethoxy-4-nitro-phenol are re-duced in a mixture o$ 18Q ml water, 10 ml of concentrated hydrochloric acid and 50 ml of acetic acid in the presence f palladium on coal catalyst. ~he catal~st is filtered and the p~ of the reaction mixture is adjusted to 6 b~ , ~addlng a 10 % sodium carbonate solution. ~he precipitated ~ubstance is filtered b~ suction~ wa~hed with wa-ter and, , covered with acetone~ ~hu~ 6 g of beige 2-ethox~-4-ami~o-phe~ol are obtained~ Yield 89 %, mp.: 192 C~
~nal~si~:
, , ", .. , . ... .. . .
~3~ 3~
- Calculated: a 62.73 Yo H 7.23 /~ N 9.14 Found: a 62.22 ~/o ~ 7.18 % N 9~08 %~
Examp~e 6 15.~1 g (001 mole) o~ 2-eth.oxy-4-am:i.no-phenol and 26 g (0.12 moles) o ethoxy-meth~lene-malonic ~cid ester are hea-ted for 2 hours on a hot wa-ter bath, thereafter 30 ml of petrol are added to the oily substance and i-t is heated under reflux for fur-ther 2 hours r On cooling a soli.d ~ubstance precipitates from the mixture of two phasesO ~he solid subs-tance is filtered and covered with petrol~ ~hus 27.78 g of beige 4-h~drox~-3-ethoxy-anili~o-me-thylene-malonic acid ester are ob-tained. Mp~: 80 C, yield 86 '~.
~nal~sis:
Calculated: a 59.43 ~/o H 6.54 % N 4.~3 %
~ound: C 5~.57 o/O ~ 6.61 % N 4.30 %.
~Z ' "`' 19.35 g (0~06 mole~) uf 4-hydroxy-3-ethoxy-a.nilino-meth~lene-malonic acid-diethyl-es-ter are he~ted in 190 ml of diph~l at 250 C for 30 mimlte6. ~he reaction mixture : 20 is cooled, and the ring-closure product is precipitated by . adding 190 ml of petrol and the product is covered with petrol~ ~hus 14~8 g of beige 6-hydroxy-7-ethoxy-4-ox~-uinollne-3-¢arboxylic acid-ethyl-ester are obtained.
ield 89~3 %, mp~: 266 a. After recrystallization from 25 : dimeth~lformamide the product melts at 270-272 C~
nal~sis: .
Calculated: a 60.64 % ~ 5~45 % N 5.05 ~/o ~ound: ~ 60.23 % H 5.55 % N 5~01~/o, _ mple 8 4.59 g (OqO3 moles) of 2-ethoxy-4-amino-phe.~ol and : . ' . , . . . . . , . . ~
3~
~ 12 _ 1OD 5~ g (0~031 moles) of ethoxy-methylene-malonic acid-di-benzyl-est-e.~ are hea-ted. for 4 hours on water bath at 100 a~
50 ml of diphyl are added and the reaction mixture ls heated for 60 minut~s at 250 C~ ~he mixture is cooled9 dilut~d with 50 ml of petrol~ the precipitated product i~ filtered and covered with alcohol. 3O4 g of brown 6-hydroxy-7-ethoxy-4-oxy--qui~oline-3-carboxylic acid-benzyl-ester are obtained.
Yield 50.2 %, mp~: 256 C.
Analysis:
aalculated: G 67.2~ % ~ 5O05 % N 4~13 %
Found: C 66.76 ~ H 4~88 % N 4.37 %~
25.52 g (0.08 moles) of 6-acetoxy-7-ethoxy-4-hydroxy~
quinoline-3-carboxyllc acid-ethyl-ester, 2000 ml of alcohol 9 200 ml of water and 240028 g (2.4 moles) of potassium . hydrogen carbonate are mixed and heated for an hourO ~he alcohol is removed in vacuo and the residual ~uspension is mixed wi~h 2000 ml of water~ ~he undissolved substance is filtered and suspended i~ wet state in 200 ml o.~ water and 2Q the .p~ of the mixture ls a~d~usted to 3 by addi~g hydrochlorlc acid of a co~centration of 5 %. ~he undissolved solid ~ubstance is filtered~ wa~hed with water, coYered with al~ohol~ Thus 16~87 g of bei~e 6-hydrox~-7-ethoxy~4-hydroxy- :
; ~ quinoline-3-carboxylic acid-eth~l-ester are obtainedO ~ield ~ ~ 76.a %~ mp:.~ 268-270 a. ~ft~r recry~tallization from di-: : methylformamide the product melt~ at 272 C.
~ample 10 . ~ .
5~54 g (0~02 moles) of 6-h~droxy-7-ethoxy-4-oxy-quinoline-3-car~ox~lic acid-ethyl-ester is mixed with the . ~olution o~ 110 ml of 80dium hydroxide solution of a con-~ 2 .
.~ .. , . , . .. ... .. ... ~ . . .... . . ... .
z~
centra-tion of 10 %7 and the mixture is heated for 3 hour~O
The reaction mixture is ~lltered at -the end of the reaction~
The filtrate is acidlf`ied to p~ 2 by adding hydrochloric acid diluted in a portion of 1~ he precipitated sub~taDce i~ filtered by suction~ and washed with wat9r~ 4085 g of white 6-hydrox~-7-ethoxy~4-oxy-quinoline-3-carb'ox~lic acid i~ obtained. Yield 97.5 /s mpO 278 C~ After recr~tallizatio~
from dimethylformamide the product melt~ at 285-287 ~.
Analysis~
Calculated: ~ 57083 % E 4.45 % N 5~62 %
Fou~d a 57.76 ~o H 4~52 ~/o N 5066 V/o.
Exa~le 11 3.06 g (0.02 moles) of 2-ethox~-4-ami~o-phenol~ 313~ g (0.02 moles) of ~-ethoxy-~carbethoxy-acrylo-~itrile are heated in 30 ml of petrol for 3 hours. ~he precipitated solld subs-tance i~ filtered and covered with pe-trol~ ~hus 5.2 g of 'beige ~(3-ethox~-4-hydrox~-anilino)-~carbethox~-acrylo-nitrlle are obtained. Yield 9.47 %, mp.~ 1~0 a.
:: a~al~i~:
Calculated~ ~ 60.85 % ,H 5.84 /0 ~ 10.14 /0 , ~ Fou~d: a 60~70 % ~ 5~98 % ~ 10.24 %~
5.52'g (0~02 mo~e~ (3~ethQx~-4-hydroxy-anillno)-4 carbeth~x~acr~lo-nltrile are heated for ~ hours in 100 ml of diph~lo On cooling a ~olid substance is precipitating from the reactio~ mixture, what is made complete by adding 100 ml of petrol. ~he produ~t is obtained is filtered and covered with petrol~ ~hu~ 2~85 g of brown 6-hydroxy-7-ethoxy-4-quinoline-3-carboxylic acid-nitrile are ob-tained~
Mp, 285 a~ ~ield &2 %. ~fter recrystallization from di-.
methyl:Eormamide the product melt~; at 336 G~
~naly~si3 ~
~alculateds a 62~60 'yO H 4~38 ~ N 12.17 %
~oulld: ( 62.30. % ~ 4~ 2 % ~ 12035 %q -: ~
: ' :
' .
' . :
.. :.~ :
Thus~ ~his invention relates to compounds of the general formula I
or Ia ~30 ~ ~ P ~30 ~ ~
R10 (Ia) R10 H (I) or a pharmaceutically acceptable acid addition or base salt thereof, ~herein R represents an alkyl group of 1 to 4 carbon atoms~ R3 represents hydrogen or an alkanoyl group of 2 to 4 carbon atoms and R4 represents -CN, -COOH
or the group -COOR ~ wherein R represents a benzyl group or an alkyl group of 1 to 4 carbon atoms.
The compounds of this invention may exist in tautomeric keto and enol forms as represented by formula (I) and (Ia).
There are several methods described for the preparation of the 6,7-dialkoxy-quinoline-carboxylic acid esters. The common feature of these methods in that as starting material 6~7-dialkoxy-derivatives are used.
~ccording to Dutch Patent Specifications Nos. 6,508,117 and $,600,447 and British Patent Specification No. 1~172~841 the 6,7-dialkoxy-4-oxy-quinoline is prepared from a 6,7-dialkoxy-4-acyloxyrquinoline-derivative.
According to an other method the 6,7-dialkoxy-4-oxy-quinolines are prepared by thermal ring-closure, where the compounds are contaminated at a high temperature with such decomposed substances which can be hardly removed. The purification of such products is very difficult as this kind ~ , B
. . . ~ . . .
~ ,.f~4~ 3~
of product is not soluble~ thus the recrystallization is greatly obstructed.
These disadv~ntages may be eliminated by the present invention.
The 6-acyloxy-derivatives according to the present invention may unexpected-ly be prepared with a very good yield by the thermal ring-closure and may be easily purified and converted into pure 6-hydro~y-quinoline-derivative~ which is suitable for further reaction.
In French Patent Specification No. 1,531,495 6-alkoxy-7-acyloxy-4-oxy~quinoline-3~carboxylic acid derivatives are described, which compounds may be considered as structural isomers of one of the compounds of the -present invention.
In French Patent Specification No 2,013~519 such 6-hydroxy-quinoline-derivatives are described, wherein a cycloalkyl group is attached to the 7-8 position of the quinoline ring.
The new 6-acyloxy and 6-hydroxy compounds of the present inYention show coccidiostatic activity themselves.
The 6-acetoxy-7-ethox~- 4Oxy-quinoline-3-carboxylic acid-ethyl-ester shows 48% activity compared to 6 n-decyloxy-7-ethoxy-4-hydroxy-3-carbethoxy-quinoline ¦A) but shows approximately the same activity as 1~2-propyl-5-amino-5-pyrimidyl-methyl-~2-methyl-pyridinium7-chloride (B) which can be regarded as a standard from the therapeutical point of view.
The 6-hydroxy-7-ethoxy-4-oxy-quinoline-3-carboxylic acid-ethyl-ester shows 54% activity, when compared with (A) and shows also about the same activity as (B).
According to one feature of the present invention, B
3~
there is provided a process for the preparation of a compound of the general formulal (I)'or (Ia)'.
OH
R30 ~ -c--~
R O (Ia) R O
or a pharmaceutically acceptable acid addition or base salt thereof, wherein R reparesents an alkyl group of 1 ~o 4 carbon atoms~ R3 represents hydrogen or an alkanoyl group of 2 to 4 carbon atoms, and R4 represents -CN, -COOH or the group -COOR , wherein R2 reprcsents a ben7yl group or an alkyl group of 1 to 4 carbon atoms; which comprises (a) subjecting a compound of the formu~a:
1 ~\ COOR2 .
R O NH-CH=C (Va) X ., wherein X is the group -CN or -COOR and wherein R , R and R3 are as de~
f - a/
fined above;~and where step (a) can be followed by the additional step of ~ ~
(b) hydrolyzing a compound of formula (I) or (Ia)oobtained in which R4 is ~: ;
: -CN or a group -COOR as hereinbefore defined to produce the corresponding compound of formula (I) or (Ia) in which R4 is the -COOH group; and where step (a) or (b) can be followed by the additional step of (~) hydrolyzing a compound of formula (I~ or (Ia~ in which R3 is an alkanoyl group to produce a corresponding compound of formula (I~ or (Ia~ in which R3 is a hydrogen ;
atom; and where step (a), (b) or (c) can be followed by the additional step ~ .
of (d) converting a base or acid of formula ~I) or (Ia~ obtained into a D -4- ::
~)4~3~ :
corresponding pharmaceutically acceptable salt by reaction with an acid or a base respectively.
As indicated above in the ~eneral formulae I and Ia R stands for a straight or branched chained alkyl group contairling 1-4 carbon atoms and is preferably an ethyl group.
Similarly, R stands for a straight or branched chained alkyl group con-taining 1-4 carbon atoms and is preferably an ethyl group as it represents a benzyl group.
R3 stands for a hydrogen atom or an alkanoyl group of 2 to 4 10carbon atoms~ which is preferably an acetoxy group.
According to an embodiment of this invention, the starting materials of formula (Va) are prepared by reacting an aniline derivative of the formula ~ (III) 1~ ' ' .
wherein R and R3 are as defined aabove~ with an ethoxymethylenemalonic acid derivative of the formula: '~
cooR2 C2H50 - CH = I (IVa) ;
.
wherein R and X are as defined above.
The compounds of formula (III) are conveniently prepared by the reduction of a corresponding nitro compound of the formula:
R 0 ~ (II) R 0 2 '~
~ a $-S- ~
~o~
wherein R and R3 are as defined above.
The compounds of the gencral formula Il~ wherein R3 stands for hydrogen are prepared according to D.F. Page and 0. Clinton: Org. Chem. 27, 218, 1962. Compounds of the general formula II~ wherein R3 stands for an alkanoyl group are prepared by alkanoylation of the hydroxy compounds.
The reduction of the compounds of the general formula II is preferably carried out by hydrogenation in the presence of a catalyst~
preferably in the presence of palladium on carbon catalyst at atmospheric pressure or under pressure.
When reducing the alkanoyl-derivatives~ the reaction is carried out in a solvent, preferably in ethyl acetateO
The reduction of the phenol of the general formula II is carried out preferably in a mixture of hydrochloric acid-water or hydrochloric acid-water-acetic acid as solvent.
The condensation of the compound of the general formula III with the compound of the general formula IVa is carried out preferably in a solvent~ particularly by boiling~e~hyl,~a¢etate~
The condensation of the hydroxy-compound of the general formula III
with the compound of the general formula IVa is also carried out in a sol-vent~ preferably in benzine under heating~ though the benzine is present rather as a diluting agent. The reaction is carried out also in the melt.
When melting the hydroxy-compound of the general formula III with the malonic acid-derivative without any solventg '' :.
~ .
B` -5a-the compound of the general formula Va need not to be isolated~ but the reaction mi~ture can be directly subjected to ring-closure in diphyl a*
250C.
According to another embodiment of the present invention the ring-c]osure of the compound of the general formula Va wherein R3 stands for hydrogen is carried out in sulphuric acid-acetic acid anhydride~ by dissolving the condensed compound in acetic acid anhydride and by adding the sulphuric acid dropwise to the solution. The temperature ~ the mixture will rise to 60 C during the addition of the sulphuric acid and the mixture will be stirred for an other 10 minutes. The product precipitates when pouring it in water.
The compounds of the general formula I, wherein R3 stands for hydrogen~ i.e. compownds of the formula IA
'''~.' "
~ :
3~
OH o HO ~ COOR HO ~ COOR
I I ~
1 ~ 1 ~ N ~ (IA) H
may also be prepared by the following methods:
A particularly pure product may be obtained~ when subjecting the compounds of the general formula I, wherein R3 stands for acyl group to selective acyl-splitting.
The acyl-splitting is carried out in a mild alkaline medium ~-preferably in the presence of potassium hydrogen carbonate in a mixture of water and alcohol at the boiling-point of the mixture. Under s~ch circum-stances the ester group remains uneffected.
According to a particular embodiment of the process of the present invention described in general terms above, the 6-hydroxy-compounds are prepared by reacting compounds of the general formulà III, wherein R stands ~-for hydrogen with ethyl-~cyano-~-ethoxy-acrylate and subjecting the com-po~md of the general formula VII
::
J~l~ ICOOC2H5 (VII) -:
R O NH-CH=C
wherein R is defined above, thus obtained to ring-closure . :
A new compound of the general formula VIII
' ' ' : , ' ' ,'"
7 .
B ~
.
3~3 0~1 0 H0 CN ~0 ~ ~ CN (VIII) R O R O
wherein R is defined above can be subjected ~o asidic or alkalin0 hydrolysis which is optionally followed by este~ification~ or the nitrile of the general formula VIII can be directly reacted with alcohol in an acidic medium.
The compounds of the general formula I, wherein R3 stands for hydrogen can be hydrolysed to thc corresponding acid. The acid obtained can be converted to another ester by reaction with the correspond~ng alcohol A base of formula Ia or I obtained can be converted to a salt, or set free from the salts thereof. The esters form salts~ for example a hydrochloride or hydrobromide salt.
The compounds of the general formula I may be a~mixed with the usual pharmaceutically acceptable carriers and used as a coccidiostatic agent.
The said coccidiostatic compositions may be finished in solid (e.g. tablets~ pills~ capsules~ granules) or liquid (e.g. solutions, emul-sions~ suspensions~ form. The compositions may be prepared by conventional method known per se and may contain the usual carriers or diluents and~ if `
necessary additives.
Further details of our invention are to be found in the Examples~
without limiting the scope of our invention to the Examples.
xample 22.5~ g (0.1 mole~ of 4-acetoxy-3-ethoxy-nitro-benzene are hydro-genated in 22.5 ml of ethyl acetate in the presence of 5 g of palladium on ;
charcoal catalyst at 5-lO atm. After the consumption of hydro~en in the desired amount, the catalyst is filtered and the reaction mixture is ! 30 evaporated to dry. On cooling crystalline 4-acetoxy-3-ethoxy-aniline is ob-tained, which is wa~hed with cold alcohol. Yield 86%, mp.: 9~ C.
Analysis:
Calculated: C 61~3 % H 6~71 % N 7017 %
~ound: C 61.30 % H 6~40 % N 6.81 %~
xample 2 25~4 g (0.1~ moles) o~ 4-ace-toxy-3-ethoxy-anlline ~re dissolved in 250 ml of ethyl acetate and 32~4 ~ ~0~15 moles) of ethoxy methylene-malonic acid diethyl-ester are added~
'~he reaction mixture is boiled for 3hours~ evaporated to dry and the residue is crystallized by cooling~ ~he substance is washed wi-th cold alcohol. ~hus white 4-acetoxy-3-ethoxy-anillno-methylene-malonic acid diethyl-ester i~
obtained with a yield of 91 %. Mp.: 102 C.
~nalysis:
Calculated; C 59~17 % H 6.34 % ~ 3.83 o/O
~ound: a 59 ~ ~ o/o H 6.50 % N 3~91 %.
1~ le 3 ~ 6~54 g (0.1 mole) o~ 4-acetox~-3-ethox~-anilino-methyle~e-malonic acid diethyl-ester are boiled in 365 ml o~ diphyl ~or 60 minutes. ~he product is successively precipitated from the reaction mixture. ~he ~uspension i~ cooled, diluted with 350 ml of petrol and filtered~
~he ~ub~tance o~ the filter is covered with pe-trol7 thus ; 25 b~ige 6-acetoxy-7-ethoxy-4-hydroxy-quinoline-~-carboxylic acid eth~l-ester is obtained. Yield 95 %9 mp.: ~00 C
(deoompo~ition). After recrystallization from dimethyl-sulfoxide the product melt~ at ~10 C~ -y9i9:
.
. .
:
~, 3~
Calculated C 6V,I8l% H 5.36 % N 4~38 %
~ound: a 60,20 '/0 H 5016 % N 4~32 %.
L~
The corresponding benzyl ester is obtained, when u~ing ethoxy-meth~len~-malo~ic acid-dibenzyl-ester instead o~
~thoxy-m~th~lene-malonic acid-dieth~l-ester. 4-acetox~-3-ethox~-aniline is reacted with ethoxy~methylene~malonic acid-dibenz~l-ester in eth~l acetate, whereafter the 6-acetoxy-7-ethoxy-4-ox~-quinoline-3 carbox~lic acid-benzyl-1Q ester is obtained without isolation of the compoundobtained a~ter evaporating the reaction mixture and after cyclisation in diphyl~ Mp.: 260 ~ (decomposition)~ ~he crude product is of beige colour~ ~fter recrystallization from dimethylformamide white cr~stalline substance is obtained. Mp.; 265 C (decomposition).
~:~al;ysis O ' .
aalculated: a 66.14 % H 5.02 % ~ ~.67 % .~
~ou~ds C 65~80 % H 5~27 % ~ 3.78 %- ;
~xample 5 2018.~1 g (0~1 mole) of 2-ethoxy-4-nitro-phenol are re-duced in a mixture o$ 18Q ml water, 10 ml of concentrated hydrochloric acid and 50 ml of acetic acid in the presence f palladium on coal catalyst. ~he catal~st is filtered and the p~ of the reaction mixture is adjusted to 6 b~ , ~addlng a 10 % sodium carbonate solution. ~he precipitated ~ubstance is filtered b~ suction~ wa~hed with wa-ter and, , covered with acetone~ ~hu~ 6 g of beige 2-ethox~-4-ami~o-phe~ol are obtained~ Yield 89 %, mp.: 192 C~
~nal~si~:
, , ", .. , . ... .. . .
~3~ 3~
- Calculated: a 62.73 Yo H 7.23 /~ N 9.14 Found: a 62.22 ~/o ~ 7.18 % N 9~08 %~
Examp~e 6 15.~1 g (001 mole) o~ 2-eth.oxy-4-am:i.no-phenol and 26 g (0.12 moles) o ethoxy-meth~lene-malonic ~cid ester are hea-ted for 2 hours on a hot wa-ter bath, thereafter 30 ml of petrol are added to the oily substance and i-t is heated under reflux for fur-ther 2 hours r On cooling a soli.d ~ubstance precipitates from the mixture of two phasesO ~he solid subs-tance is filtered and covered with petrol~ ~hus 27.78 g of beige 4-h~drox~-3-ethoxy-anili~o-me-thylene-malonic acid ester are ob-tained. Mp~: 80 C, yield 86 '~.
~nal~sis:
Calculated: a 59.43 ~/o H 6.54 % N 4.~3 %
~ound: C 5~.57 o/O ~ 6.61 % N 4.30 %.
~Z ' "`' 19.35 g (0~06 mole~) uf 4-hydroxy-3-ethoxy-a.nilino-meth~lene-malonic acid-diethyl-es-ter are he~ted in 190 ml of diph~l at 250 C for 30 mimlte6. ~he reaction mixture : 20 is cooled, and the ring-closure product is precipitated by . adding 190 ml of petrol and the product is covered with petrol~ ~hus 14~8 g of beige 6-hydroxy-7-ethoxy-4-ox~-uinollne-3-¢arboxylic acid-ethyl-ester are obtained.
ield 89~3 %, mp~: 266 a. After recrystallization from 25 : dimeth~lformamide the product melts at 270-272 C~
nal~sis: .
Calculated: a 60.64 % ~ 5~45 % N 5.05 ~/o ~ound: ~ 60.23 % H 5.55 % N 5~01~/o, _ mple 8 4.59 g (OqO3 moles) of 2-ethoxy-4-amino-phe.~ol and : . ' . , . . . . . , . . ~
3~
~ 12 _ 1OD 5~ g (0~031 moles) of ethoxy-methylene-malonic acid-di-benzyl-est-e.~ are hea-ted. for 4 hours on water bath at 100 a~
50 ml of diphyl are added and the reaction mixture ls heated for 60 minut~s at 250 C~ ~he mixture is cooled9 dilut~d with 50 ml of petrol~ the precipitated product i~ filtered and covered with alcohol. 3O4 g of brown 6-hydroxy-7-ethoxy-4-oxy--qui~oline-3-carboxylic acid-benzyl-ester are obtained.
Yield 50.2 %, mp~: 256 C.
Analysis:
aalculated: G 67.2~ % ~ 5O05 % N 4~13 %
Found: C 66.76 ~ H 4~88 % N 4.37 %~
25.52 g (0.08 moles) of 6-acetoxy-7-ethoxy-4-hydroxy~
quinoline-3-carboxyllc acid-ethyl-ester, 2000 ml of alcohol 9 200 ml of water and 240028 g (2.4 moles) of potassium . hydrogen carbonate are mixed and heated for an hourO ~he alcohol is removed in vacuo and the residual ~uspension is mixed wi~h 2000 ml of water~ ~he undissolved substance is filtered and suspended i~ wet state in 200 ml o.~ water and 2Q the .p~ of the mixture ls a~d~usted to 3 by addi~g hydrochlorlc acid of a co~centration of 5 %. ~he undissolved solid ~ubstance is filtered~ wa~hed with water, coYered with al~ohol~ Thus 16~87 g of bei~e 6-hydrox~-7-ethoxy~4-hydroxy- :
; ~ quinoline-3-carboxylic acid-eth~l-ester are obtainedO ~ield ~ ~ 76.a %~ mp:.~ 268-270 a. ~ft~r recry~tallization from di-: : methylformamide the product melt~ at 272 C.
~ample 10 . ~ .
5~54 g (0~02 moles) of 6-h~droxy-7-ethoxy-4-oxy-quinoline-3-car~ox~lic acid-ethyl-ester is mixed with the . ~olution o~ 110 ml of 80dium hydroxide solution of a con-~ 2 .
.~ .. , . , . .. ... .. ... ~ . . .... . . ... .
z~
centra-tion of 10 %7 and the mixture is heated for 3 hour~O
The reaction mixture is ~lltered at -the end of the reaction~
The filtrate is acidlf`ied to p~ 2 by adding hydrochloric acid diluted in a portion of 1~ he precipitated sub~taDce i~ filtered by suction~ and washed with wat9r~ 4085 g of white 6-hydrox~-7-ethoxy~4-oxy-quinoline-3-carb'ox~lic acid i~ obtained. Yield 97.5 /s mpO 278 C~ After recr~tallizatio~
from dimethylformamide the product melt~ at 285-287 ~.
Analysis~
Calculated: ~ 57083 % E 4.45 % N 5~62 %
Fou~d a 57.76 ~o H 4~52 ~/o N 5066 V/o.
Exa~le 11 3.06 g (0.02 moles) of 2-ethox~-4-ami~o-phenol~ 313~ g (0.02 moles) of ~-ethoxy-~carbethoxy-acrylo-~itrile are heated in 30 ml of petrol for 3 hours. ~he precipitated solld subs-tance i~ filtered and covered with pe-trol~ ~hus 5.2 g of 'beige ~(3-ethox~-4-hydrox~-anilino)-~carbethox~-acrylo-nitrlle are obtained. Yield 9.47 %, mp.~ 1~0 a.
:: a~al~i~:
Calculated~ ~ 60.85 % ,H 5.84 /0 ~ 10.14 /0 , ~ Fou~d: a 60~70 % ~ 5~98 % ~ 10.24 %~
5.52'g (0~02 mo~e~ (3~ethQx~-4-hydroxy-anillno)-4 carbeth~x~acr~lo-nltrile are heated for ~ hours in 100 ml of diph~lo On cooling a ~olid substance is precipitating from the reactio~ mixture, what is made complete by adding 100 ml of petrol. ~he produ~t is obtained is filtered and covered with petrol~ ~hu~ 2~85 g of brown 6-hydroxy-7-ethoxy-4-quinoline-3-carboxylic acid-nitrile are ob-tained~
Mp, 285 a~ ~ield &2 %. ~fter recrystallization from di-.
methyl:Eormamide the product melt~; at 336 G~
~naly~si3 ~
~alculateds a 62~60 'yO H 4~38 ~ N 12.17 %
~oulld: ( 62.30. % ~ 4~ 2 % ~ 12035 %q -: ~
: ' :
' .
' . :
.. :.~ :
Claims (30)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of a compound of the general formula (I) or (Ia):
(I) 1 or a pharmaceutically acceptable acid addition or base salt thereof, wherein R1 represents an alkyl group of 1 to 4 carbon atoms, R3 represents hydrogen or an alkanoyl group of 2 to 4 carbon atoms, and R4 represents -CN, -COOH
or the group -COOR2, wherein R2 represents a benzyl group or an alkyl group of 1 to 4 carbon atoms; which comprises (a) subjecting a compound of the formula:
(Va) wherein X is the group -CN or -COOR2 and wherein R1, R2 and R3 are as defined above; to ring-closure and where step (a) can be followed by the additional step of (b) hydrolyzing a compound of formula (I)1 or (Ia)1 obtained in which R4 is -CN or a group -COOR2 as hereinbefore defined to produce the corres-ponding compound of formula (I)' or (Ia)' in which R4 is the -COOH group; and where step (a) or (b) can be followed by the additional step of (c) hydro-lyzing a compound of formula (I)' or (Ia)' in which R3 is an alkanoyl group to produce a corresponding compound of formula (I)' or (Ia)' in which R3 is a hydrogen atom; and where step (a), (b) or (c) can be followed by the additional step of (d) converting a base or acid of formula (I)' or (Ia)' obtained into a corresponding pharmaceutically acceptable salt by reaction with an acid or a base respectively.
(I) 1 or a pharmaceutically acceptable acid addition or base salt thereof, wherein R1 represents an alkyl group of 1 to 4 carbon atoms, R3 represents hydrogen or an alkanoyl group of 2 to 4 carbon atoms, and R4 represents -CN, -COOH
or the group -COOR2, wherein R2 represents a benzyl group or an alkyl group of 1 to 4 carbon atoms; which comprises (a) subjecting a compound of the formula:
(Va) wherein X is the group -CN or -COOR2 and wherein R1, R2 and R3 are as defined above; to ring-closure and where step (a) can be followed by the additional step of (b) hydrolyzing a compound of formula (I)1 or (Ia)1 obtained in which R4 is -CN or a group -COOR2 as hereinbefore defined to produce the corres-ponding compound of formula (I)' or (Ia)' in which R4 is the -COOH group; and where step (a) or (b) can be followed by the additional step of (c) hydro-lyzing a compound of formula (I)' or (Ia)' in which R3 is an alkanoyl group to produce a corresponding compound of formula (I)' or (Ia)' in which R3 is a hydrogen atom; and where step (a), (b) or (c) can be followed by the additional step of (d) converting a base or acid of formula (I)' or (Ia)' obtained into a corresponding pharmaceutically acceptable salt by reaction with an acid or a base respectively.
2. Process according to claim 1 in which the starting material of formula (Va) is prepared by reacting an aniline derivative of the formula:
(III) wherein R1 and R3 are as defined in claim 1, with an ethoxymethylenemalonic acid derivative of the formula:
(IVa) wherein R2 and X are as defined in claim 1.
(III) wherein R1 and R3 are as defined in claim 1, with an ethoxymethylenemalonic acid derivative of the formula:
(IVa) wherein R2 and X are as defined in claim 1.
3. Process according to claim 2 in which the product obtained is not isolated but subjected in situ to ring-closure.
4. Process according to claim 2 or 3 in which the starting material of formula (III) is prepared by the reduction of the corresponding nitro compound of the formula:
(II) wherein R1 and R3 are as defined in claim 2.
(II) wherein R1 and R3 are as defined in claim 2.
5. Process according to claim 4 in which the reduction is effected by hydrogenation in the presence of palladium or carbon as catalyst.
6. Process according to claim 2 in which the reaction of the com-pounds of formulae (III) and (IVa) is carried out by heating in a solvent.
7. Process according to claim 1 in which the ring-closure is carried out by heating in a solvent of high boiling point.
8. Process according to claim 1 in which the ring-closure is effected by heating in diphyl or paraffin.
9. Process according to claim 1(c), in which the hydrolysis is effected in a mild alkaline medium.
10. Process according to claim 9 in which the mild alkaline medium is potassium hydrogen carbonate in aqueous alcohol and hydrolysis is effected at the boiling point of the mixture.
11. Process according to claim 1 in which R4 represents the group -COOR2, wherein R2 is as defined in claim 1.
12. Process according to claim 11 in which R3 represents an alkanoyl group of 2 to 4 carbon atoms.
13. Process according to claim 1 in which R3 is a hydrogen atom and R4 represents the group -COOR2, wherein R2 is as defined in claim 11.
14. Process according to claim 1 in which R1 is ethyl, R3 is a hydrogen atom, X is the group -COOR2 and R2 is an ethyl group.
15. Process according to claim 1 for the preparation of 6-hydroxy-7-ethoxy-4-oxyquinoline-3-carboxylic acid-ethyl ester which comprises sub-jecting 4-hydroxy-3-ethoxyanilinomethylene-malonic acid diethyl ester to ring-closure.
16. Process according to claim 1 in which R1 is ethyl, R3 is a hydrogen atom, X is the group -COOR2 and R2 is a benzyl group.
17. Process according to claim 1 for the preparation of 6-hydroxy-7-ethoxy-4-oxyquinoline-3-carboxylic acid benzyl ester which comprises sub-jecting 4-hydroxy-3-ethoxyanilinomethylene-malonic acid dibenzyl ester to ring-closure.
18. Process according to claim 1 in which R1 is ethyl, R3 is the acetoxy group, X is the group -COOR2 and R2 is an ethyl group.
19. Process according to claim 1 in which 6-acetoxy-7-ethoxy-4-hydroxyquinoline-3-carboxylic acid ethyl ester is prepared by subjecting 4-acetoxy-3-ethoxyanilinomethylene-malonic acid diethyl ester to ring-closure.
20. Process according to claim 19 in which the product obtained is subjected to mild alkaline hydrolysis to produce 6-hydroxy-7-ethoxy-4-hydroxyquinoline-3-carboxylic acid ethyl ester.
21. Process according to claim 20 in which the hydrolysis is effected by heating with a solution of potassium hydrogen carbonate in aqueous alcohol.
22. Process according to claim 1 in which R1 is ethyl, R3 is the ace-toxy group, X is the group -COOR2, and R2 is the benzyl group.
23. Process according to claim 1 in which 6-acetoxy-7-ethoxy-4-oxyquinoline-3-carboxylic acid benzyl ester is prepared by subjecting 4-acetoxy-3-ethoxyanilinomethylene-malonic acid dibenzyl ester to ring-closure
24. A compound of the formula (I)' or (Ia)' as defined in claim 1 or a pharmaceutically acceptable acid addition or base salt thereof whenever prepared by the process of claim 1, 2 or 3 or by an obvious chemical equivalent thereof.
25. A compound of the formula (I)' or (Ia)' given in claim 1 in which R4 represents the group -COOR2 and wherein R2, R1 and R3 are as defined in claim 1 whenever prepared by the process of claim 11 or by an obvious chemical equivalent thereof.
26. A compound of the formula (I)' or (Ia)' given in claim 1 in which R3 represents an alkanoyl group of 2 to 4 carbon atoms, R4 represents the group -COOR2 and wherein R1 and R2 are as defined in claim 1 whenever prepared by the process of claim 12 or by an obvious chemical equivalent thereof.
27. 6-Hydroxy-7-ethoxy-4-oxyquinoline-3-carboxylic acid ethyl ester whenever prepared by the process of claim 15, 20 or 21 or by an obvious chemical equivalent thereof.
28. 6-Hydroxy-7-ethoxy-4-oxyquinoline-3-carboxylic acid benzyl ester whenever prepared by the process of claim 17 or by an obvious chemical equivalent thereof.
29. 6-Acetoxy-7-ethoxy-4-hydroxyquinoline-3-carboxylic acid ethyl ester whenever prepared by the process of claim 19 or by an obvious chemical equivalent thereof.
30. 6-Acetoxy-7-ethoxy-4-oxyquinoline-3-carboxylic acid benzyl ester whenever prepared by the process of claim 23 or by an obvious chemical equivalent thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HUCI001404 HU167573B (en) | 1973-08-28 | 1973-08-28 | |
| HUCI001403 HU167572B (en) | 1973-08-28 | 1973-08-28 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1044239A true CA1044239A (en) | 1978-12-12 |
Family
ID=26318396
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA207,894A Expired CA1044239A (en) | 1973-08-28 | 1974-08-27 | 6-alkoxy-7-hydroxyquinoline-3-carboxylic acids and derivatives thereof |
Country Status (13)
| Country | Link |
|---|---|
| JP (1) | JPS5082077A (en) |
| AT (1) | AT338789B (en) |
| CA (1) | CA1044239A (en) |
| CH (1) | CH615917A5 (en) |
| DD (1) | DD114077A1 (en) |
| DK (1) | DK141167B (en) |
| GB (1) | GB1467225A (en) |
| IN (1) | IN140826B (en) |
| NL (1) | NL7411324A (en) |
| NO (1) | NO145788C (en) |
| PL (1) | PL92578B1 (en) |
| SE (1) | SE406911B (en) |
| SU (1) | SU567402A3 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE4014171A1 (en) * | 1990-05-03 | 1991-11-07 | Basf Ag | cyanoquinoline |
-
1974
- 1974-08-23 SE SE7410745A patent/SE406911B/en unknown
- 1974-08-26 AT AT688374A patent/AT338789B/en not_active IP Right Cessation
- 1974-08-26 NL NL7411324A patent/NL7411324A/en not_active Application Discontinuation
- 1974-08-26 PL PL1974187261A patent/PL92578B1/pl unknown
- 1974-08-27 GB GB3745174A patent/GB1467225A/en not_active Expired
- 1974-08-27 JP JP49098309A patent/JPS5082077A/ja active Pending
- 1974-08-27 DK DK454774AA patent/DK141167B/en not_active IP Right Cessation
- 1974-08-27 NO NO743064A patent/NO145788C/en unknown
- 1974-08-27 CA CA207,894A patent/CA1044239A/en not_active Expired
- 1974-08-27 CH CH1168574A patent/CH615917A5/en not_active IP Right Cessation
- 1974-08-27 SU SU7402057994A patent/SU567402A3/en active
- 1974-08-28 DD DD180757A patent/DD114077A1/xx unknown
- 1974-08-28 IN IN1940/CAL/1974A patent/IN140826B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| NO145788B (en) | 1982-02-22 |
| PL92578B1 (en) | 1977-04-30 |
| DK454774A (en) | 1975-04-28 |
| SE406911B (en) | 1979-03-05 |
| GB1467225A (en) | 1977-03-16 |
| NO743064L (en) | 1975-03-24 |
| DK141167B (en) | 1980-01-28 |
| IN140826B (en) | 1976-12-25 |
| DK141167C (en) | 1980-06-23 |
| NO145788C (en) | 1982-06-02 |
| DD114077A1 (en) | 1975-07-12 |
| NL7411324A (en) | 1975-03-04 |
| SE7410745L (en) | 1975-03-03 |
| JPS5082077A (en) | 1975-07-03 |
| AT338789B (en) | 1977-09-12 |
| CH615917A5 (en) | 1980-02-29 |
| SU567402A3 (en) | 1977-07-30 |
| ATA688374A (en) | 1977-01-15 |
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