Note: Descriptions are shown in the official language in which they were submitted.
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:
R30
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
R30
~ (III)
1~ ' ' .
R 0 NH
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)
R 0 R 0
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
H0
::
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-
23
- 9
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~
I - 10 -
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~
- 13
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
-: ~
: ' :
'
.
'
. :
.. :.~ :
