US2338569A - Preparation of coumarin-3-carboxylic acid - Google Patents
Preparation of coumarin-3-carboxylic acid Download PDFInfo
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- US2338569A US2338569A US396190A US39619041A US2338569A US 2338569 A US2338569 A US 2338569A US 396190 A US396190 A US 396190A US 39619041 A US39619041 A US 39619041A US 2338569 A US2338569 A US 2338569A
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- coumarin
- carboxylic acid
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- acid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
- C07D311/08—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring
- C07D311/12—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring substituted in position 3 and unsubstituted in position 7
Definitions
- This invention concerns the condensation of aromatic aldehydes with malonic acid and more particularly improvements in the method for the condensation of salicylaldehyde with malonic acid to form coumarin-B-carboxylic acid.
- Stuarts method consists in heating together a mixture of salicylaldehyde, malonic acid, and glacial acetic acid at 100 0., followed by recrystallization of the coumarin-B-carboxylic acid.
- German Patent 161,171 equimolecular proportions of salicylaldehyde and malonic acid are heated for several hours on the water bath with 0.13 molecular proportion of aniline hydrochloride
- German Patent 97,735 equimolecular proportions of malonic acid and aniline are heated on the water bath with 0.87 molecular proportion of salicylaldehyde.
- the reaction mixture employed in our process contains as essential ingredients, malonic acid, salicylaldehyde, an amine or an amine salt, e. g., aniline, meta-toluidine, para-aminophenol, salicylidene aniline, aniline hydrochloride, etc., as catalyst, and a water-entraining agent, e. g., hexane, ethylene dichloride, benzene, monochlor-benzene, isopropyl ether, etc.
- the mixture may also contain acetic acid or other lower aliphatic carboxylic acid, e. g., propionic acid, etc., but its presence is not required.
- the salicylaldehyde and malonic acid are ordinarily used in substantially equimolecular proportions, i. e., in the proportions in which they react together, but the reaction may be carried out using a large excess of either reactant, if desired.
- Anhydrous reactants are preferred but are not essential since any water introduced into the reaction mixture with the reactants subsequently co-distills with the water-entraining agent.
- aromatic amines are usually employed, preferably aniline. It is probable that when amines are used they are converted by the acid in the reaction mixture into the corresponding salt.
- the relationship between yield and reaction temperature is illustrated in the table given in Example 2.
- waterentraining agents which may be used to remove water from the reaction mixture are hydrocarbons, halohydrocarbons, ethers, etc.
- Water-en training agents which are chemically inert toward the reactant under the reaction conditions are' preferred.
- the reaction temperature is, of course, that at which water and the entraining agent distill from the mixture, which temperature is usually somewhat, though not greatly, lower than the boiling point of the entraining agent alone.
- water-entraining agents whose boiling points at atmospheric pressure are lower or higher than the desired reaction temperature may be used, in which case the pressure under which the reaction is carried out is increased or decreased, respectively, to cause the entraining agent to boil at the desired reaction temperature.
- An amount of the entraining agent sufficient to maintain the reaction mixture in a semifluid condition is used advantageously. Entraining agents.
- a water-immiscible entraining agent may advantageously be used, since such agent may be continuously separated from the distillate and returned to the reaction vessel. Alternatively, successive portions of the agent may be added at intervals to replace that distilled or a sufiicient amount may be added-to the original reaction mixture to carry over substantially all of the water while maintaining the reaction mixture in the desired state of fluidity.
- the reaction is complete when water is no longer carried over by the entraining agent. This usually occurs after from 3 to hours of heating and distilling, but the time depends to a considerable extent, of course, on the boiling point of the water entraining agent and the rate of distillation.
- the mixture may be cooled and filtered to separate the cournarin-3-carboxylic acid, and the latterwashed with fresh portions of the entraining agent until substantially free from the amine and acetic acid.
- the washed coumarin-B-carboxylic acid may be dried, e. g., in a current of warm air, and'after drying is substantially pure.
- the combined filtrate may be dried, e. g., in a current of warm air, and'after drying is substantially pure.
- EXAMPLE 2 The results of a number of experiments on the preparation of coumarin-B-carboxylic acid using water-entraining agents with diiferent boiling.
- reaction mixtures containing equimolecular proportions of salicylaldehyde, malonic acid, and acetic acid, together with 0.02 molecular proportion of aniline and approximately 200 cc. of the entraining agent noted to each mol of salicylaldehyde were heated to cause smooth distillation until water ceased distilling with the entraining agent.
- the mixtures were then cooled and filtered and the coumarin-3- carboxylic acid washed with fresh portions of the entraining agent and dried.
- the reaction temperature and time, the boiling point of the water-entraining agent used, the per cent yield, and the melting point of the coumarin-3-carboxylic acid isolated are noted for each experiment:
- a method for preparing coumarin-3-carboxylic acid the steps which consist in heating a mixture comprising substantially equimolecular proportions of salicylaldehyde and malonic acid, not to exceed 0.1 molecular proportion of an amine and a water-immiscible water-entraining agent boiling between about 50 and about 85 C. to co-distill the entraining agent and Water from the reacting mixture and separating coumarin-3- carboxylic acid from the reacted mixture.
- a method of preparing coumarin-3-carboxylic acid the steps which consist in heating a mixture comprising substantially equimolecular proportions of salicylaldehyde and malonic acid, not to exceed 1 molecular proportion of acetic acid, not to exceed 0.05 molecular proportion of aniline, and a petroleum fraction boiling between about 60 C. and about 70 C. to co-distill the petroleum fraction and water from the reacting mixture, separating coumarin-3-carboxylic acid from the reacted mixture, and washing and drying the coumarin-B-carboxylic acid.
- a method of preparing coumarin-B-carboxylic acid the steps which consist in heating a mixture comprising substantially equimolecular proportions of salicylaldehyde and malonic acid, not to exceed 1 molecular proportion of acetic acid, not to exceed 0.05 molecular proportion of aniline, and isopropyl ether to co-distill the isopropyl ether and Water from the reacting mixture, separating coumarin-B-carboxylic acid from the reacted mixture, and washing and drying the coumarin-3-carboxylic acid.
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Description
Patented Jan. 4, 1944 7 2,338,569 PREPARATION OF ooUMARm-s- CARBOXYLIC ACID Luther F. Berhenke, Ezra Monroe, and Edgar C. Britton, Midland, Mich., assignors to The Dow Chemical Company, Midland, Mich., a corporation of Michigan No Drawing. Application May 31, 1941, Serial No. 396,190
4 Claims.
This invention concerns the condensation of aromatic aldehydes with malonic acid and more particularly improvements in the method for the condensation of salicylaldehyde with malonic acid to form coumarin-B-carboxylic acid.
The preparation of coumarin-3-carboxylic acid by the condensation of salicylaldehyde with malonic acid is well known (cf. Stuart: J. Chem. Soc. 49 366 (1886); and German Patents Nos: 161,171, 164,296, and 97,735). According to these teachings, this condensation has heretofore been accomplished by heating salicylaldehyde and malonic acid together in the presence of amines, amine salts, or acetic acid at temperatures approximating 100 C. German Patent 164,296 describes the use of piperidine as a catalyst with a resultant yield of 80 per cent of coumarin-ZB-carboxylic acid. Stuarts method consists in heating together a mixture of salicylaldehyde, malonic acid, and glacial acetic acid at 100 0., followed by recrystallization of the coumarin-B-carboxylic acid. According to German Patent 161,171 equimolecular proportions of salicylaldehyde and malonic acid are heated for several hours on the water bath with 0.13 molecular proportion of aniline hydrochloride, and according to German Patent 97,735 equimolecular proportions of malonic acid and aniline are heated on the water bath with 0.87 molecular proportion of salicylaldehyde.
Disadvantages inherent in these known meth ods are apparent. .The large amount of either acetic acid or catalyst such as amine or amine salt which it is necessary to employ necessitates purification, e. g., recrystallization, of the coumarin-3-carboxylic acid which involves considerable expense and lowering in yield. Furthermore, in the condensation to form the coumarin- 3-carboxylic acid two molecular proportions of water are formed. As is known, malonic acid is unstable in the presence of water at temperatures as low as 70 0., being converted slowly into acetic acid and carbon dioxide. The rate of decomposition increases rapidly with rise in temperature, so that a substantial portion of the malonic acid is lost through decomposition when the reaction is carried out as usual at a temperature of approximately 1 C. Knoevenagel (Ber. 31 2618 (1898)) attempted to overcome this difiiculty by allowing equimolecular proportions of malonic acid, salicylaldehyde, and aniline to stand in alcoholic solution at room temperature for 24 hours, but obtained only an 80 per cent yield of coumarin-B-carboxylic acid. We have attempted repeatedly to prepare coumarin-3-carboxylic acid in good yield by the procedures given in the literature using equimolecular proportions of salicylaldehyde andmalonic acid at elevated temperatures, but'in no case was a yield of crude material greater than 91.5 per cent' obtained based upon the malonic acid used. This yield is, of course, lowered upon crystallizing to secure a pure product.
It is an object of this invention to provide an improved method for the preparation of coumarin-B-carboxylic acid, whereby the yield is substantially improved over that possible with previously known methods and by means of which a product sufficiently pure for most uses can be obtained directly from the reaction mixture without resorting to additional purification steps.
We have found that these objects may be attained by dispersing salicylaldehyde, malonic acid, and small amounts of amines or amine salts in a liquid water-entraining agent and heating to a temperature sufiicient to co-distill the entraining agent and the water formed during the reaction, followed by separation and washing of the coumarin-S-carboxylic acid product. We have further found that although the reaction may be carried out at widely varying temperatures it occurs most satisfactorily when carried out at temperatures between about 40 C. and about C.
As just indicated, the reaction mixture employed in our process contains as essential ingredients, malonic acid, salicylaldehyde, an amine or an amine salt, e. g., aniline, meta-toluidine, para-aminophenol, salicylidene aniline, aniline hydrochloride, etc., as catalyst, and a water-entraining agent, e. g., hexane, ethylene dichloride, benzene, monochlor-benzene, isopropyl ether, etc. The mixture may also contain acetic acid or other lower aliphatic carboxylic acid, e. g., propionic acid, etc., but its presence is not required.
The salicylaldehyde and malonic acid are ordinarily used in substantially equimolecular proportions, i. e., in the proportions in which they react together, but the reaction may be carried out using a large excess of either reactant, if desired. Anhydrous reactants are preferred but are not essential since any water introduced into the reaction mixture with the reactants subsequently co-distills with the water-entraining agent. Although a large number of amines and their salts have been found effective as catalysts for the reaction, aromatic amines are usually employed, preferably aniline. It is probable that when amines are used they are converted by the acid in the reaction mixture into the corresponding salt. It may be mentioned that the continuous removal of water from the reacting mixture, in accordance with the invention, favors completion of the reaction and permits employment of the catalyst in amount considerably less than the amounts used in prior methods for the production of coumarin-3-carboxylic acid. Less than 10.0 mol per cent of aniline or other amine is used and preferably less than 5.0 mol per cent,
100 C., and preferably between 50 and 85C.
The relationship between yield and reaction temperature is illustrated in the table given in Example 2. Among the various well-known waterentraining agents which may be used to remove water from the reaction mixture are hydrocarbons, halohydrocarbons, ethers, etc. ,Water-en training agents which are chemically inert toward the reactant under the reaction conditions are' preferred. The reaction temperature is, of course, that at which water and the entraining agent distill from the mixture, which temperature is usually somewhat, though not greatly, lower than the boiling point of the entraining agent alone. However, water-entraining agents whose boiling points at atmospheric pressure are lower or higher than the desired reaction temperature may be used, in which case the pressure under which the reaction is carried out is increased or decreased, respectively, to cause the entraining agent to boil at the desired reaction temperature. An amount of the entraining agent sufficient to maintain the reaction mixture in a semifluid condition is used advantageously. Entraining agents.
in which coumarin-3-carboxylic acid is relatively insoluble are preferred since they permit excellent recovery of the product by simply cooling and filtering the reacted mixture. A water-immiscible entraining agent may advantageously be used, since such agent may be continuously separated from the distillate and returned to the reaction vessel. Alternatively, successive portions of the agent may be added at intervals to replace that distilled or a sufiicient amount may be added-to the original reaction mixture to carry over substantially all of the water while maintaining the reaction mixture in the desired state of fluidity.
It has been found advantageous to include a minor proportion of a saturated monobasic aliphatic acid such as acetic or propionic acids in the reaction mixture since the presence of such acids leads to somewhat smoother reaction and the isolation of a slightly purer product. The function of the monobasic acid may be to act as a solubilizing agent for the malonic acid. 0.25'to 1.0 molecular proportion of acetic acid has been used with advantage.
The reaction is complete when water is no longer carried over by the entraining agent. This usually occurs after from 3 to hours of heating and distilling, but the time depends to a considerable extent, of course, on the boiling point of the water entraining agent and the rate of distillation. When the reaction is complete, the mixture may be cooled and filtered to separate the cournarin-3-carboxylic acid, and the latterwashed with fresh portions of the entraining agent until substantially free from the amine and acetic acid. The washed coumarin-B-carboxylic acid may be dried, e. g., in a current of warm air, and'after drying is substantially pure. The combined filtrate. and washings may be saved and used in subsequent reactions for the production of coumarin-B-carboxylic acid. Since substantially all of the acetic acid and amine used are found in the filtrate and washings, it is only necessary to add enough of each to replace that lost during the process.
By carrying the reaction out as just described,
coumarin-B-carboxylic acid of good purity may readily be produced in nearly quantitative yield.
The following examples describe a number of ways in which the principle of the invention has n been applied, but are not to be construed as limiting its scope.
EXAMPLE 1 t 122 grams (1 mol) of salicylalclehyde, 104 grams (1 mol) of malonic acid, 15.8 grams (0.26 mol) of acetic acid, 2 grams (.02 mol) of aniline, and 250 cc. of petroleum ether (n-hexane fraction boiling at 60'70 C.) were heated together. Co-distillation of water and petroleum ether occurred at 60-65 C. The distillate was condensed and the petroleum ether wa separated from the water and returned continuously to the reaction flask. As the reaction progressed, the coumarin-3-carboxylic acid precipitated from the mixture to form a thick slurry. After 8 hours of heating, water was no longer distilling together with the petroleum ether. The reaction mixture was then cooled and filtered. The coumarin-3-carboxylic acid was washed on the filter with fresh petroleum ether, until substantially free from aniline and acetic acid and dried. There was thus obtained grams (1 mol) of substantially pure coumarin-3-carboxylic acid melting at 184-188 C. The combined filtrate and washings were saved and used in a subsequent reaction.
EXAMPLE 2 The results of a number of experiments on the preparation of coumarin-B-carboxylic acid using water-entraining agents with diiferent boiling.
points are given in the following table. In obtaining this data, reaction mixtures containing equimolecular proportions of salicylaldehyde, malonic acid, and acetic acid, together with 0.02 molecular proportion of aniline and approximately 200 cc. of the entraining agent noted to each mol of salicylaldehyde were heated to cause smooth distillation until water ceased distilling with the entraining agent. The mixtures were then cooled and filtered and the coumarin-3- carboxylic acid washed with fresh portions of the entraining agent and dried. The reaction temperature and time, the boiling point of the water-entraining agent used, the per cent yield, and the melting point of the coumarin-3-carboxylic acid isolated are noted for each experiment:
TABLE Efiect of boiling point of water-entraining agent on yield of coumarin-3-carboxylic acid Other modes of applying the principle of the invention may be employed instead of those explained, change being made as regards the process herein disclosed, provided the step or steps stated by any of the following claims or the equivalent of such stated step or steps be employed.
We therefore particularly point out and distinctly claim as our invention:
1. In a method for preparing coumarin-3-carboxylic acid, the steps which consist in heating a mixture comprising substantially equimolecular proportions of salicylaldehyde and malonic acid, not to exceed 0.1 molecular proportion of an amine and a water-immiscible water-entraining agent boiling between about 50 and about 85 C. to co-distill the entraining agent and Water from the reacting mixture and separating coumarin-3- carboxylic acid from the reacted mixture.
2. In a method of preparing coumarin-3-carboxylic acid the steps which consist in heating a mixture comprising substantially equimolecular proportions of salicylaldehyde and malonic acid, not to exceed 1 molecular proportion of acetic acid, not to exceed 0.05 molecular proportion of aniline, and a petroleum fraction boiling between about 60 C. and about 70 C. to co-distill the petroleum fraction and water from the reacting mixture, separating coumarin-3-carboxylic acid from the reacted mixture, and washing and drying the coumarin-B-carboxylic acid.
3. In a method of preparing coumarin-B-carboxylic acid the steps which consist in heating a mixture comprising substantially equimolecular proportions of salicylaldehyde and malonic acid, not to exceed 1 molecular proportion of acetic acid, not to exceed 0.05 molecular proportion of aniline, and isopropyl ether to co-distill the isopropyl ether and Water from the reacting mixture, separating coumarin-B-carboxylic acid from the reacted mixture, and washing and drying the coumarin-3-carboxylic acid.
4. In a method of preparing coumarin-B-carboxylic acid the steps which consist in heating a mixture comprising substantially equimolecular proportions of salicylaldehyde and malonic acid,
not to exceed 1 molecular proportion of acetic acid, not to exceed 0.05mo1ecular proportion of aniline, and benzene to co-distill the benzene and water from the reacting mixture, separating coumarin-3-carboxylic acid from the reacted mixture, and washing and drying the coumarin- 3-carboxylic acid.
LUTHER. F. BERHENKE.
EZRA MONROE.
EDGAR C. BRITTON.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US396190A US2338569A (en) | 1941-05-31 | 1941-05-31 | Preparation of coumarin-3-carboxylic acid |
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| US396190A US2338569A (en) | 1941-05-31 | 1941-05-31 | Preparation of coumarin-3-carboxylic acid |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9093202B2 (en) | 2011-06-08 | 2015-07-28 | Hubbell Incorporated | Elastomeric gripping member for spacer assembly |
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1941
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9093202B2 (en) | 2011-06-08 | 2015-07-28 | Hubbell Incorporated | Elastomeric gripping member for spacer assembly |
| US9570216B2 (en) | 2011-06-08 | 2017-02-14 | Hubbell Incorporated | Elastomeric gripping member for spacer assembly |
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