PREPARATION OF ESTERS OF 3-CARBOXY-4-HYDROXY-QUINOLINE OR NAPHTHYRIDINE COMPOUNDS

ESTERS DE COMPOSES DE CARBOXY-3 HYDROXY-4 QUINOLINE OU NAPHTYRIDINE

English Abstract

ABSTRACT OF THE DISCLOSURE:
Esters of 3-carboxy-4-hydroxy-quinoline or naphthyridine
compounds having the general formula:
<IMG> (I)
wherein R1 is N- or -CH-; R2 is alkyl containing 1 to 4 carbon
atoms; R3 and R4 are identical or different and each represents
alkyl containing 1 to 4 carbon atoms, alkoxy containing 1 to 4
carbon atoms or halogen, or R3 and R4 together form -O-CH2-O-,
are prepared by bringing a solution of a compound having the
general formula:
<IMG>
wherein R1, R2, R3 and R4 have the aforesaid meanings, in an
organic solvent having a boiling point at or above a predetermined
cyclization temperature, into contact at a temperature of about
120° to 200°C with the same organic solvent which is at a
temperature such that the cyclization temperature of the mixture
is about 200° to 350°C for a period of time sufficient for the
cyclization and then quickly cooling the reaction mixture to
produce the desired compound of the formula (I). The process
enables one to obtain product yields as high as 97%, while avoiding
undesirable secondary reactions.

Claims

The embodiments of the invention in which an exclusive
property or privilege is claimed are defined as follows:
1. A process for the preparation of esters of 3-carboxy-
4-hydroxy-quinoline or naphthyridine compounds having the general
formula:
<IMG> (I)
wherein:
R1 is -N- or -CH-;
R2 is alkyl containing 1 to 4 carbon atoms;
R3 and R4 are identical or different and each represents
alkyl containing 1 to 4 carbon atoms, alkoxy containing 1 to 4
carbon atoms or halogen, or R3 and R4 together form -O-CH2-O-,
which comprises bringing a solution of a compound having the
general formula:
<IMG>
(II)
wherein R1, R2, R3 and R4 have tne aforesaid meanings, in an
organic solvent having a boiling point at or above a predetermined
cyclization temperature, into contact at a temperature of about
120° to 200°C with the same organic solvent which is at a
temperature such that the cyclization temperature of the mixture
is about 200° to 350°C for a period of time sufficient for the
cyclization and then quickly cooling the reaction mixture to
produce the desired compound of the formula (I).
11

2. Process according to claim 1, wherein the solution
of the starting compound is mixed with a quantity of the organic
solvent preheated to a temperature of from 240 to 360°C such that
the resulting reaction mixture has a temperature of from 200 to
350°C.
3. Process according to claim 2, wherein the temperature
of the resulting reaction mixture is comprised between 240 and
330°C.
4. Process according to claim 1, wherein the solution
o the starting compound is at a temperature of from 140 to 160°C.
5. Process according to claim 2, wherein the quantity
of preheated organic solvent used is from 2 to 12 times the
quantity of solution used.
6. Process according to claim 5, wherein the quantity
of preheated organic solvent used is from 5 to 10 times the
quantity of solution used.
7. Process according to claim 1, wherein the organic
solvent used is selected from the group comprising diphenyl-
benzene, dibenzylbenzene, ditolyl, diphenylethane, triphenyl-
methane, tetraphenylmethane, benzophenone and terephthalic acid
dimethyl ester.
8. Process according to claim 1, wherein the reaction
mixture is maintained at the cyclization temperature with vigorous
stirring in a stirrer-equipped vessel provided with means for
maintaining the reaction mixture at the required temperature.
9. Process according to claim 8, wherein the reaction
mixture is stirred by means a stirrer rotating at a speed of from
50 to 300 rpm.
12

10. Process according to claim 8, wherein the vessel
used for the ring-closure reaction is a tube reactor.
11. Process according to claims 8 or 10, wherein
subsequent to the cyclization, the reaction mixture is quenched
by passage through a heat exchanger.
12. Process according to claim 1, wherein subsequent
to the cyclization, the reaction mixture is quenched by intro-
duczion into a low-boiling inert solvent.
13. Process according to claim 12, wherein the low-
boiling inert solvent used is an ether, a ketone, an ester, an
aliphatic hydrocarbon containing from 1 to 6 carbon atoms, or
an aromatic hydrocarbon containing from 6 to 10 carbon atoms.
14. Process according to claims 12 or 13, wherein the
low-boiling inert solvent is used in a quantity of from 1 to 5
times the quantity of reaction mixture.
13

Description

iOSI~OZki
~ le present in~ention relates to a process for
preparing a cyclisate by effecting, in an organic solvent, a
ring-closure reaction of a compound capable of undergoing such
a reaction when heated in the solvent. The reaction takes place
by the elimination of a radical from the compound undergoing
the ring-closure reaction.
The process of the invention is particularly suitable
for carrying out ring-closure reactions which o~ly ta~e place at
relatively high temperatures above those which can ~e attained
with conventional solvents. Thus, the process according to the
invention is particularly suitable for carrying out ring-closure
reactions of the kind in which an alcohol, derived from an
ester group, is éliminated from the compound undergoing ring-
closure. Hitherto, reactions of this kind have never been
completely controlled, because numerous secondary reactions and
competitive reactions reduce the yield and contaminate the re-
quired end product at the high temperature at which the alcohol
is eliminated and the ring-closure reactions take place. For
example, it is known that 1,8-naphthyridine derivatives can
be obtained by cyclising 2-pyridylaminomethylene malonic acid
esters, the reaction being accompanied by the elimination of
alcohol. However, according to R. Lappin, J. Am. Chem. Soc.
70 (1948), 334~, 7-methyl-4-hydroxy-3-carbethoxy-l,~ naphthyridine
can only be o~tained in good yields by adding the methylpyridy-
laminomethylene malonic acid diethylester to a solution of
diphenylether bolling under reflux at about 260~C, and cooling
the reaction mixture as quickly as possible after a reaction
time of 10 minutes. In this process, small quantities of around
0.1 mol give good yields, whilst Lappin obtains "without excep-
tion much lower yields" with larger batches. Our own tests
have shown that, despite rapid cooling, the yield falls to
around 45 to 55 /O of the theoreti~al yield when quantities of
diethylester greater than 20 g are used.
.

~C~510~)Z~
Acco~ding -to the presen-t invention, there is provided a
process for preparing cyclisates, and more particularly esters
of 3-carboxy-4-hydroxy-quinoline or naphthyridine compounds having
the general formula:
~H ..
4 ~ ~ C ~ OR2
3 l N (I)
H
wherein:
Rl is -N- or -CH-;
R2 is alkyl containing l to 4 carbon atoms;
R3 and R4 are identical or different and each represents
alkyl containing l to 4 carbon atoms, alkoxy containing l to 4
carbon atoms or halogen, or R3 and R4 together form -O-CH2-O-.
The process o the invention comprises bringing a solution of a
compound having the general formula:
O O
R O-C C-OR
4 ~ C
~ R l N ~ (II)
R3
wherein Rl, R2, R3 and R4 have the aforesaid meani.ngs, in an
orgànic solvent having a boiling point at or above a predetermined
cyclization temperature, into contact at a temperature of about
120 to 200C with the same organic solvent which is at a
temperature such that the cyclization temperature of the mixture
is about 200 to 350C for a period of time sufficient for the
cyclizati~n and then quickly cooling the reaction mixture to
produce the desired compound of the formula (I).
-- 2

la~so~zG
~ ccording to a prefer~ed embodiment, the solution of the
starting compound is mixed with a large quantity of -the high-
boiling organic solvent preheated to a temperature of from 240 to
360C such th~t the resulting reaction mixture has a temperature
of from 200 to 350C.
The process according to the invention is suprising
in that it is usually possible, on a commercial scale, to obtain
high yields of at least 80%, often up to as much as 97%, of the
cyclisates from the starting compounds. The process can be,
and is preferably, carried out continuously with exact residence
times which can be between a few minutes up to about half an hour.
In order to obtain optimum yields and to avoid secondary
reactions, it is generally necessary to adhere to a certain,
strictly defined reaction time during cyclisation, which time is
governed to a certain extent both by the cyclising temperature
and by the type of apparatus used. It is essential to avoid
re-admixture, so that each quantity of suhstance always remains
in the apparatus for the same, optimum reaction time.
A short heating time is important, in particular for
avoiding secondary reactions, and can be obtained by heating a
pre-prepared solution of the starting compound in the high-
- boiling solvent to a temperature at which neither the cyclising
reaction nor secondary reactions take place~ and subsequently
introducing this solution into a generally larger quantity of
the high-boiling solvent which is heated to a temperat~lre higher
than the cyclising temperature.
The cyclising temperature, which is determined by the
differcnce in temperature betwccn the solution and thc highly
heated solvent and by th~ quantities in which they are used,
is generally in the range from 200 to 350C, preferably in the
range from 2~0 to 330C.
~ - 3 -
,~,

1~500~;
The tempera-ture of the pre-prepared solution of the
starting compound is generally 120 to 200C, and preferably 140
to 160 C. The ratio of the quantity of the preheated high-boiling
solvent can vary somewhat according to the difference between
the temperature of the solution and the cyclising temperature.
In general, however, the high-boiling solvent is used in 2 to 12
times the quantity, preferably in 5 to 10 times the quantity,
of the solution of starting material.
Since the high-boiling solvents must boil at or above
the cyclising temperature, but must not themselves take part
in the reaction and should not undergo any appreciable
decomposition, even after pxolonged use and on recovery, there are
only a few high-boiling solvents which can be used. Examples of
such solvents are high-boiling aromatic hydrocarbons, preferably
polynuclear aromatic hydrocarbons, e.g. diphenylbenzene, dibenzyl-
benzene and ditolyl; araliphatic hydrocarbons, e.g. diphenyl-
ethane, triphenylmethane and tetraphenylmethane: aromatic
ketones, e.g. benzophenone; and aromatic carboxyl acid esters,
e.g. terephthalic acid dimethyl ester.
- 3a -
~ .

~500~
The reaction can be carried out in one vessel or in
two or more reaction vessels arranged in series. When only one
reaction vessel is used, the reaction is carried out in batches,
in which case the solution starting material and the preheated
solvent are introduced into the vessel, followed by a period o~
admixture and reaction, and by quenching, In general, admixture
is preferably carried out by intense stirring ~ith a highly
effective, high-speed stirre~.
In cases where several reactors are used, they are
preferably in the ~orm of autoclaves, the first acting as a
mixing vessel. After a residence of, for example, a ~ew minutes
in one reactor, the reaction mixture is transferred to the next.
qhe contents of the first or, preferably, all the reactors are
being stirred, and the reaction mixture is discharged from the
last reactor for quenching.
A stirrer speed of 50 to 300 rpm, in some cases up to
1000 rpm, is preferably used for the vessels.
It is best to provide the reaction vessel or vessels
with a condenser, with a temperature-measuring means, with valves
for introducing starting solution and solvent, with an emptying
valve and with a heating and cooling system for maintaining the
contents of the vessel at the desired temperature.
In ordet to produce a relatively large quantity of
product, it is preferred to carry out the process continuously
in view of the short reaction time. The reactor should be
designed in accordance with the optimum cyclising time.
In ~eneral, the residence time and hence the cyclising
time are set in advance, and the reaction controlled by selecting
the cyclising temperature~ The cyclising temperature in turn
depends upon the temperatures of the solution and solvent and
upon the quantities in which they are used.
Quenching the reaction solution by a sudden, drastic
reduction in temperature is preferably carried out with relatively
` : :: ., . ::

OOZ6
lo~-boiling inert liquids, e.g. ket~nes, esters or hydrocarbons,
preferably aliphatlc or aromatic hydrocarbons with 6 to lO
carbon atoms. In general~ -t~e inert liquids are used in 1 to 5
times the quantity of reaction mixture. The effect of cooling
can be enhanced by evapora-ting the inert liquid.
In addition, it can be of advantage to pass the reaction
mixture through a heat exchanger for rapid cooling. The reaction
mixture diluted with the liquids is subjected to extrac-tion,
and filtered or centrifuged in known manner after cooling.
Another, similarly pure, fraction of the product can generally be
obtained from the mother liquor by concentrating the solven-t.
The solvents used can readily be separated by virtue of the
considerable difference between their boiling points, and can be
re-used.
The process of the in-~ention, which is generally
carried out at temperatures of from 200 to 360C, is particularly
suitable for the production of polynuclear heterocyclic compounds
the hetero cyclic rings of which contain one or more nitrogen
atoms, for example 4-hydroxy-3-carbalkoxynaphthyridines and
quinolines optionally carrying further substituents, from the
correspondingly substituted or unsubstituted pyridyl- and phenyl-
aminomethylene malonic esters. These further substituents can be
situated in any unoccupied positions of the rings and can be of
any type, with the proviso that they are unable to take any part in
the cyclising reaction. ~xamples of such further substituents
are alkyl and alkoxy groups, especially those with l to 4 carbon
atoms; aromatic groups, especially phenyl groups; halogen atoms,
especially chlorine atoms; phenolic hydroxyl groups; and alkyl
substituents optionally containing alcohol-, keto- or ether-
groups.
Temperatures in the range from 250 to 310C andcyclising times of about 8 to 15 minutes, more especially a~out lO

1~'50C~Z6
minutes, have proved to be par-ticularly suitable for producing
the naphthyridine and quinoline derivatives.
At temperatures below 250C, the reaction takes longer
and is accompanied by the formation of increasingly larger
~uantities of undesirable secondary products which have to be
removed by subsequent recrystallisa-tion. Yield-reducing secondary
products are also formed at temperatures above 330C despite
the somewhat shorter reaction times.
Cyclisation of the naphthyridine derivatives and
quinoline derivatives can be carried out either continuously
or in batches. To produce the naphthyridine or quinoline
derivatives, it is best to heat the high-boiling solvents to around
280 - 340C and to mix them in a 10-fold to 17-fold quantity with
a solution heated to 120 - 150C of the starting substance in the
high-boiling solvent.
. The naphthyridine and quinoline derivatives are inter-
mediate products for the production of, for example, hair dyes.
The process according to the invention will now be
better illustrated with reference to the following non-restrictives
examples:
EXAMP~E 1
Batch production of 7~methyl-4-hydroxy-3-carbethoxy-1,8-naphthy-
--.

~05~026
ridine .
A 250 litre capacity ~eaction vessel was filled with
150 kg of dibenzylbenzene, which was then heated with stirring
to a temperature of approximately 330C. A solution~ heated
to 120 - 150C, of 10 kg of methylpyridylaminomethylene malonic
acid diethyl ester (PMME) in 25 kg of dibenzylbenzene was added
over a period of about 0,5 to 1 minute to the dibenzylbenzene
heated to 330C. During the reaction, ethanol diqtilled off
from the reaction mixture. Cyclisation was over after 10 minu-
tes at 300C. The reaction mixture was passed quickly through
a heat exchanger into a hexane-filled cooling vessel where
considerable heat was dissipated both hy external cooling and
by evaporation cooling. The cyclisate crystallising out was
separated off in a centrifuge. The filter cake was washed re-
peatedly with hexane and the washing liquid combined with the
filtrate. The hexane was separated off from this solution by
distillation. The mother liquor remaining in the sump of the
distillation column was repeatedly delivered to the next batch
until it had to ~e free from the secondary products. The yield
of desired product was 92 % of the theoretical yield, based
on PMME.
EXAMPLE-2
Continuous production of 7-methyl-4-hydroxy-3-carbethoxY-1,8-
naphthyridine
This compound was continuously produced in an 80 litre
capacity tube reactor. A quantity of 300 litres per hour of
; divinylbenzene was heated to-330C, and delivered continuously
to the reactor in admixture with a solution, heated to 150C,
of 20 kg of PMME in 50 kg of divinylbenzene. The temperature
of the reaction mixture was kept at 300C. After a reaction
time of around 10 minutes, the reaction product was continuously
run off, cooled in a heat exchanger and diluted with approximately
--7--

~s~o~
1000 litres of hexane per hour. After cooling, the cyclisate
crystallising out was separated off in a centrifuge and washed
as described in Example 1. An average of about 15.4 kg per
hour of the desired product were produced, which corresponds to
a yield of 93 % of the theoretical yield, hased on PMMEo
EXAMPLE 3
Batch production of 3-carbethoxy-4-hy~_oxY-7-chloro-l-quinoline
150 litres of divinylbenzene were heated with stirring
to 300C in a 250 litre capacity vessel. A solution, heated to
150C, of 15kg of _-chlorophenylaminomethylene malonic acid
diethyl ester in 25 litres of of divinylbenzene was added to the
hot divinylbenzene over a period of 1 minute. The ethanol formed
during the reaction immediately distilled off. The reaction was
over after about 10 to 12 minutes. ~he reaction mixture was
then quickly cooled and the cyclisate which precipitated was
filtered off. The filter cake was washed repeatedly with hexane
and then driedt The filtrate and washing liquid were treated in
the same way as described in Example 1. The yield of 3-carbetoxy-
4-hydroxy-7-chloro-1-quinoline was 95 % of the theoretical yield,
based on m-chlorophenylaminomethylene malonic acid diethyl
- ester.
XAMPLE 4
3-Carbethoxy-4-hydroxYquinoline
150 litres of dibenzylbenzene were heated to approxi-
mately 320C in a 250 litre vessel equipped with a stirrer. A
solution, heated to 150C, of 13.2 kg of anilinomethylene malonic
acid diethyl ester in 25 kg of dibenzylbenzene was added with
vigorous stirring over a period of 1 to 2 minutesO The ethanol
formed distilled off immediately. The reaction was over after
about 10 minutes. The reaction mixture was quickly cooled,
whereupon the cyclisate crystallised out of the still warm solu- -
tion. Filtration, washing and treatment of the filtrate were

~SOOZ6
carried out in the same way as described in Example 1~ l~e yield
of 3-carbethoxy-4-hydroxy-quinoline was 9.9kg, corresponding to
91 % of the theoretical yield~
EXAMPLE 5
3-Carbethoxy-4-hydroxy-6,7-d1 thoxYquinoline
150 litres of dibenzylbenzene were heated to approxi-
mately 300~C in a 250 litre vessel equipped with a stirrer. A
solution, heated to 150C, of 12.5 kg of 3,4-dimethoxyanilinome-
thylene malonic acid diethyl ester in 25 kg of diben~ylbenzene
was added with vigorous stirring over a perlod of 1 to 2 minutes.
The ethanol formed distilled off immediately. The reaction was
over after about 12 minutes. The reaction mixture was quickly
cooled. The cyclisate crystallised out of the still warm
solution. Filtration, washing and treatment of the filtrate were
carried out in the same way as described in Example 3. The
yield of 3-carbethoxy-4-hydroxy-6,7-dimethoxyquinoline was 10 kg,
corresponding to 93.5 % of the theoretical yield.
EXAMPLE 6
3-Carbethox~-4-hYdroxy-6,7 methylendioxyquinoline
75 litres of dibenzylbenzene were heated to approxi-
matively 300C in a 150 litre vessel equipped with a stirrer.
A solution, heated to 150~C, of 6.0 k~ of 3,4-methylendioxy-
anilinomethylene malGnic acid diethylester in 12 kg of dibenzyl-
benzene was added with vigourous stirring over a period of 1 to
2 minutes. 'rhe ethanol formed distilled off immediately. The
reaction was over after about 12 to 18 minutes. The reaction
mixture was quickly cooled ; the cyclisate crystallized out of
the still warm solution. Filtration, washing and treatment
of the filtrate was carried out as described in Example 5.
4.8 kg of 3-Carbethoxy-4-hydroxy-6,7 methylendioxyquinoline
was obtained (95%,yield), in which compound the 3,4- methylen-
dioxy group of formula -0-CH2-O- together with the carbon atoms

~5~
to which it is attached, form the ring ^
/o f 7
H2C~
o _ C 6
In a corresponding manner, N-ethyl-3,4~methylendioxy-
anilonomethylene malonic acid diethylester may be transformed
into N-ethyl-3-carbethoxy-4-oxo-6,7-methylendioxyquinoline.
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