CA1050026A - Preparation of esters of 3-carboxy-4-hydroxy-quinoline or naphthyridine compounds - Google Patents
Preparation of esters of 3-carboxy-4-hydroxy-quinoline or naphthyridine compoundsInfo
- Publication number
- CA1050026A CA1050026A CA207,985A CA207985A CA1050026A CA 1050026 A CA1050026 A CA 1050026A CA 207985 A CA207985 A CA 207985A CA 1050026 A CA1050026 A CA 1050026A
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- Prior art keywords
- temperature
- process according
- reaction mixture
- cyclization
- carbon atoms
- Prior art date
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Classifications
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Thin Film Transistor (AREA)
- Junction Field-Effect Transistors (AREA)
- Pyridine Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Quinoline Compounds (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE:
Esters of 3-carboxy-4-hydroxy-quinoline or naphthyridine compounds having the general formula:
(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:
Esters of 3-carboxy-4-hydroxy-quinoline or naphthyridine compounds having the general formula:
(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:
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) 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).
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 ` : :: ., . ::
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.
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 ~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 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.
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~
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.
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
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) 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).
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 ` : :: ., . ::
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.
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 ~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 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.
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~
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.
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.
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.
Claims (14)
1. A process for the preparation of esters of 3-carboxy-4-hydroxy-quinoline or naphthyridine compounds having the general formula:
(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:
(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).
(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:
(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).
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.
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.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE2343462A DE2343462C2 (en) | 1973-08-29 | 1973-08-29 | Process for the preparation of cyclic compounds from an ester by ring closure reactions |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1050026A true CA1050026A (en) | 1979-03-06 |
Family
ID=5890990
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA207,985A Expired CA1050026A (en) | 1973-08-29 | 1974-08-28 | Preparation of esters of 3-carboxy-4-hydroxy-quinoline or naphthyridine compounds |
Country Status (13)
| Country | Link |
|---|---|
| JP (1) | JPS5050380A (en) |
| BE (1) | BE819195A (en) |
| CA (1) | CA1050026A (en) |
| CH (1) | CH599074A5 (en) |
| DK (1) | DK139968C (en) |
| ES (1) | ES429588A1 (en) |
| FI (1) | FI251874A (en) |
| FR (1) | FR2245584B1 (en) |
| GB (1) | GB1443620A (en) |
| HU (1) | HU169039B (en) |
| IT (1) | IT1021613B (en) |
| NL (1) | NL7411274A (en) |
| SE (1) | SE402273B (en) |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2504875A (en) * | 1945-06-04 | 1950-04-18 | Us Sec War | Method for producing 4-hydroxyquinolines |
-
1974
- 1974-08-23 CH CH1155274A patent/CH599074A5/de not_active IP Right Cessation
- 1974-08-23 NL NL7411274A patent/NL7411274A/en not_active Application Discontinuation
- 1974-08-26 BE BE147914A patent/BE819195A/en unknown
- 1974-08-27 JP JP49098315A patent/JPS5050380A/ja active Pending
- 1974-08-28 CA CA207,985A patent/CA1050026A/en not_active Expired
- 1974-08-28 SE SE7410896A patent/SE402273B/en unknown
- 1974-08-28 FI FI2518/74A patent/FI251874A/fi unknown
- 1974-08-28 FR FR7429397A patent/FR2245584B1/fr not_active Expired
- 1974-08-28 IT IT7452773A patent/IT1021613B/en active
- 1974-08-28 HU HUDI255A patent/HU169039B/hu unknown
- 1974-08-28 DK DK457874A patent/DK139968C/en active
- 1974-08-28 GB GB3769374A patent/GB1443620A/en not_active Expired
- 1974-08-28 ES ES429588A patent/ES429588A1/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| SE402273B (en) | 1978-06-26 |
| DK139968C (en) | 1979-11-05 |
| FR2245584A1 (en) | 1975-04-25 |
| SE7410896L (en) | 1975-03-03 |
| DK457874A (en) | 1975-04-28 |
| DK139968B (en) | 1979-05-28 |
| FR2245584B1 (en) | 1978-02-17 |
| HU169039B (en) | 1976-09-28 |
| ES429588A1 (en) | 1976-09-16 |
| JPS5050380A (en) | 1975-05-06 |
| NL7411274A (en) | 1975-03-04 |
| FI251874A (en) | 1975-03-01 |
| GB1443620A (en) | 1976-07-21 |
| CH599074A5 (en) | 1978-05-12 |
| IT1021613B (en) | 1978-02-20 |
| BE819195A (en) | 1974-12-16 |
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