PREPARATION OF 6,7-DIALKOXY-4-OXY-QUINOLINE- 3 CARBOXYLIC ACID ESTER COMPOUNDS

PREPARATION DES COMPOSES DE L'ESTER DE L'ACIDE DIALKOXY,6,7-EXYQUINOLEINE,4-CARBOXYLIQUE

English Abstract

ABSTRACT OF THE DISCLOSURE
This invention relates to a process for the preparation of
6,7-dialkoxy-4-oxyquinoline-3-carboxyl acid-esters of the general formula:
<IMG> (I)
wherein R1 stands for a C1-4 alkyl group, R2 stands for an alkenyl or
alkyl group, containing 3-12 carbon atoms, and R3 stands for a C1-4
alkyl or phenyl-C1-4 alkyl group, which comprises alkylating a compound
of the general formula II:
<IMG> (II)
wherein R1 and R3 are as defined above.

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. Process for the preparation of 6,7-dialkoxy-4-oxy-quinoline-3-
carboxylic acid esters of the general formula I
<IMG> (I)
wherein R1 stands for a C1-4 alkyl group, R2 stands for an alkenyl or
alkyl group, containing 3-12 carbon atoms, and R3 stands for C1-4 alkyl
or phenyl-C1-4-alkyl group, which comprises alkenylating or alkylating a
compound of the general formula II
<IMG> (II)
wherein R1 and R3 are defined as above.
2. Process according to claim 1, which comprises carrying out the
alkenylation or alkylation with an alkenylating or alkylating agent of
high boiling point.
3. Process according to claim 1, which comprises carrying out the
reaction in the presence of an acid-binding agent.
4. Process according to claim 1, which comprises carrying out the
reaction in an organic solvent at 50°- 100°C.
5. Process according to claim 1 in which the alkenylation or
alkylation is carried out with an alkenyl or alkyl halide.

6. A process according to claim 5 in which the alkenyl or alkyl
halide is alkyl, n-butyl or n-decyl bromide.
7. Process according to claim 1 in which 6-n-decyloxy-7-ethoxy-4-
hydroxyquinoline-3-carboxylic acid ethyl ester is prepared by reacting
6-hydroxy-7-ethoxy-4-oxyquinoline-3-carboxylic acid ethyl ester with n-decyl
bromide.
8. Process according to claim 1 in which 6-n-decyloxy-7-ethoxy-
quinoline-3-carboxylic acid benzyl ester is prepared by reacting 6-hydroxy-
7-ethoxy-4-oxyquinoline-3-carboxylic acid benzyl ester with n-decyl bromide.
9. Process according to claim 1 in which 6-n-butoxy-7-ethoxy-4-
oxyquinoline-3-carboxylic acid ethyl ester is prepared by reacting 6-
hydroxy-7-ethoxy-4-oxyquinoline-3-carboxylic acid ethyl ester with n-butyl
bromide.
10. Process according to claim 1 in which 6-allyloxy-7-ethoxy-4-
oxyquinoline-3-carboxylic acid ethyl ester is prepared by reacting 6-
hydroxy-7-ethoxy-4-oxyquinoline-3-carboxylic acid ethyl ester with allyl
bromide.
11. Process according to claim 3 in which the acid-binding agent is
sodium hydride.

Description

~)41515
The present invention is directed to a new process for the
preparation of known 6,7-dialkoxy-4-oxy-quinoline-3-carboxylic acid
esters of the general formula I
OH O
R O ~ CoOR3 R O ~ COOR (I)
wherein R stands for a C1 4 alkyl group, R stands for an alkenyl or
alkyl group containing 3-12 carbon atoms and R3 stands for a C1 4 alkyl
or phenyl-C1 4-alkyl group.
The compounds of the formula I are known coccidiostatica.
According to the literature the 6~7-dialkoxy-4-oxy-quinoline~
3-carboxylic acid derivatives have been prepared from 3,4-dialkoxy-
aniline derivatives, i.e. the corresponding dialkoxy-groups have been --
formed on the benzene ring.
Thus~according to British Patent Specification No. 1~188,364
and French Patent Specification No. 1,531,495 4-decyloxy-3-ethoxy-aniline
is condensed with ethoxy-methylene-malon ester (EMME), and the desired
6,7-dialkoxy-substituted quinoline derivative is prepared by subjecting
the compound thus obtained to ring~closure.
According to German Patent Specification No. 1,954,189 3,4-di-
isobutoxy-anilino-methylene-malon-ester is subjected to ring-closure.
According to German Patent Specification No. 2,058,002 3,4-
dialkoxy-aniline is reacted with ortho-formic acid ester and p-toluene-
sulphonic acid to yield 6,7-dialkoxy-quinoline derivatives. 6,7-dialkoxy-
4-hydroxy-quinoline-
qF
. . ~ , .
!:'., ~. "' '
' : , . . ,:. :
:

l`C~4151S
ester compounds are prepared from 6,7-dialkoxy-4-chloro-quinoline-3-
carboxylic acid ester accordinglto USP Specification No. 3~665~oo5.
According to the above mentioned "traditional" methods 6,7-di-
alkoxy-4-hydroxy-quinoline-3-carboxylic acid derivatives were prepared
from 3,4-dialkoxy-aniline derivatives.
According to the present invention there is provided a process
for the preparation of 6,7-dialkoxy-4-oxy-quinoline-3-carboxylic acid
derivatives of the general formula I by alkenylating or alkylating the
compounds of the general formula II
OH o
HO ~ CoOR3 HO ~ CoOR3
ll 1 l (II)
Rl ~ ~ A`N ~ 1 ~ ~ ~ N~
H ~-
wherein R and R are defined as above.
The disadvantage of the process wherein the coccidiostatic ~
4-oxy-3-carbalkoxy-quinolines were prepared by thermal cyclization is, -
that the cyclization takes place at 250 & and thus due to decomposition the
product is contaminated and canno~be easily purified. These compounds
'; ' ,' ' ' '.
are generally insoluble and the repeated recrystallizations are accompanied
with several losses.
According to the present invention the alkylation is preferably ~;-
carried out in a solvent which can be used for the purification of the
product as well. The preferred reaction temperature is 50-100~C, which is
achieved by using water-bath.
From the point of view of the product, it is of great importance,
that the last step of the entire synthesis is not a thermal ring-closure,
but an alkylation carried out at lower temperature.
~3~
, . .
.
. , ::-
-.
, ~ :

16~41515
The compounds of the general formula II exist in tautomeric
keto- and enol forms.
In the formula I R stands for a straight or branched chain
lower alkyl group containing 1-4 carbon atoms, preferably a methyl or
ethyl group.
R stands for an alkenyl or alkyl group containing 3-12 carbon
atoms, preferably a n-butyl, n-decyl or allyl group.
R stands for alkyl group containing 1-4 carbon atoms, preferably
an ethyl group, or a phenyl-C1 4 alkyl group~ preferably a benzyl group.
The alkylation of the new compounds of the general formula II
is preferably carried out with an alkylating agent of high boiling point,
most preferably with alky~ halidès. Othèr alkylating agents of high
boiling point e.g. p-toluene-sulphonic acid ester may also be used.
The alkylation is preferably carried out in the presence of an
acid-binding agent, preferably in the presence of sodium hydride. Other
acid binding agents e.g. potassium carbonate may also be used.
According to an advantageous embodiment of the present invention
the reaction is carried~lout in an organic solvent, preferably in
dimethylformamide.
The reaction may be carried out by heating the reactio~mLxture
on a water-bath of a temperature of 100 C, but other temperature inter-
vals as 50-15~ C (boiling-point of dimethylformamide) may be applied as
well. At a lower temperature the reaction gets very slow.
Further details of the present invention are to be found in the
Examples without limiting the scope of the in-
,.,

1~41515
vention to the Examples.
Example 1
1.38 g (0.005 moles) of 6-hydroxy-7-ethoxy-4-oxy-quinoline-3-
carboxylic acid ethyl ester are suspended in 60 ml of warm dimethylformamide,
whereafter 0.5 g (0.01 mole) of oily sodium hydride suspension are added at
50C, the latter was flushed with 10 ml of dimethylformamide.
After adding of 1.32 g (0.006 moles) of n-decylbromide the tempera-
ture of the waterbath is elevated to 100C and the mixture is stirred for
20 hours. The mixture is evaporated to dryness in vacuo, the residue is
taken up in 40 ml of water and the pH of the suspension is adjusted to neutral
by adding of diluted hydrochloric acid. me precipitated substance is fil-
tered and covered with water. 1.47 g of beige 6-n-decyloxy-7-ethoxy-4-
hydroxy-quinoline-3-carboxylic acid ethyl-ester are obtained. Mp.: 230-232C.
Yield: ?1 %. After recrystallization from dimethylformamide white product `
is obtained which melts at 242-244C.
Exam~le 2
Accordir,g to the method described in Example 1, 6-decyloxy-7-
ethoxy-quinoline-3-carboxylic acid-benzyl-ester is obtained. Mp. of the crude
product is 198C~ after recrystallization the product melts at 202-203C.
Analysis:
Calculated: C 72.62 % H 7.78 % N 2.92 %
Found: C 72.78 % H 7.93 % N 3.04 %.
_xample 3
2.76 g (0.01 mole) of 6-hydroxy-7-ethoxy-4-oxy-quinoline-3-carboxylic
acid-ethyl-ester are stirred in 120 ml of warm dimethylformamide, 1.0 g
(0.02 moles) of oily sodium hydride suspension is added to the mixture at ;
50C, the suspension is flushed with 20 ml of dimethylformamide. After adding
1.64 g (0.012 moles) of n-butyl-bromide the temperaturè of waterbath is
successively elevated to 100C and at this temperature the mixture is stirred
- 5 -
.. . .. .; .

1~34151S
for 30 hours. After the reaction time the mixture is evaporated to dry in
vacuo and the residue is taken up in 40 ml of water. The pH is adjusted to
neutral by adding diluted hydrochloric acid and the precipitated solid sub-
stance is filtered, covered with water, thus 3.1 g of 6-n-butoxy-7-ethoxy-
4-oxy-quinoline-3-carboxylic acid-ethyl-ester is obtained. Mp.: 220C.
Yield: 93.2 %. After recrystallization the product melts at 257C.
Example 4
The process is the same when reacting the 6-hydroxy-derivative with
allyl-bromide, but the reaction time will be 50 hours. Thus 6-allyl-oxy-7-
ethoxy-4-oxyquinoline-3-carboxylic acid-ethyl-ester is obtained with a yield
of 91.5 %. Mp.: 220C. After recrystallization from dimethylformamide the
product melts at 233C.