US3171842A - Preparation of gamma pyrones - Google Patents
Preparation of gamma pyrones Download PDFInfo
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- US3171842A US3171842A US202102A US20210262A US3171842A US 3171842 A US3171842 A US 3171842A US 202102 A US202102 A US 202102A US 20210262 A US20210262 A US 20210262A US 3171842 A US3171842 A US 3171842A
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- maltol
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/34—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D309/36—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
- C07D309/40—Oxygen atoms attached in positions 3 and 4, e.g. maltol
Definitions
- the present invention relates to a process for the preparation of gamma-pyrones. More particularly it is concerned With an improved process for the preparation of maltol, 3-hydroxy-2-methyl-4-pyrone, a particularly valuable gamma-pyrone, which is useful, among other things, for its flavor and aroma-enhancing properties.
- maltol is obtained commercially from wood, for example, by difficult and expensive extraction processes, it is known to the art that it can also be obtained by chemical syntheses from other gamma-pyrones.
- kojic acid 2-hydroxymethyl-5- hydroxy-4-pyrone
- step (1) in the reaction sequence is 43% and in step (2) the highest yield is reported to be 17%; thus an overall yield of maltol of only 7.3% based on It is noteworthy that after many experiments, this low yield was only obtained after conducting the reduction at a very high pressure (100 atmospheres) and in the presence of an expensive noble metal catalyst (palladium-on-charcoal).
- Z-dimethylaminomethylpyromeconic ac Z-di-n-butylamino-pyromeconic acid and 2-morpholin methylpyromeconic acid are examples of Z-di-su'ostitute aminomethylpyromeconic acids which are especially u: ful.
- metal-acid reducing agent e01 binations as employed herein and in the appended chain it is meant, as is obvious to those skilled in the art, co] binations of acids with metals appropriately located the electromotive series of the elements, which combir tions provide a reducing action on organic compount As will be discussed in connection with the process, a.
- the ter metal-acid reducing agent combinations contemplated metals, for example, zinc, iron, aluminum, tin, magne um, and the like, and as acids, strong mineral acids su as, for example, hydrochloric acid and sulfuric acid, a monocarboxylic saturated open-chain aliphatic acids tl have from 1 to 10 carbon atoms and which are soluble the reaction system, such acid being represented by, t example, formic acid, acetic acid, isodecanoic acid, a the like.
- the 2 di-substituted-arninomethylpyromeconic aci may be conveniently prepared by reaction of pyron conic acid with a mixture of formaldehydeand an orgar amine such as, for example, dimethylamine, di-n-but amine, piperidine, morpholine, and the like.
- Pyrorr conic acid may be obtained as is described in the Sa copending application, for example, by decarboxylati of comenic acid Which is in turn obtained by oxidation commercially-available kojic acid.
- the reaction C0111 tions suitable for formation of the Mannich base deriy from piperidine are described in the aforementiom Spielman et al. article.
- the mixture is treated with an aunt of metal such as, for example, zinc, iron, alumin, tin, magnesium, and the like, equivalent to from 111: 1.2 to about 2.5 gram atoms of metal per mole of nnich base;
- the resulting suspension is treated with the 1 member of the reducing agent combination .and 1:he ction mixture is maintained at a temperaturepf fr m ut to about 125 ;C.,.preferably, to minimize side ctions, from-about .25 toabout 75 ,C.,,and especially Eerably at about 5565 C., until paper chromatophic assay indicates .the 2-di-substitutedaminomethylomeconic .acid to have been substantially completely :s-umed.
- Maltol canbeisolated from-the-reaction mixa by adjusting thepI-I to from about ,1 tOgfilbOllt 3 and racting ,theacidic solution with about 5 volumes of organic solvent such as, for example, chloroform, er, benzene, and the like. Concentration of the oric layer causes crystallinemaltol to precipitate. This be removed byfiltration.
- the metal to be employed .i-ntheimproved processrof present invention must'be appropriately located in electromotive series to react with the acid ,-1 nember ention may be any strong mineral acid or mono- I boxylicsaturated open-chain aliphatic acids of from a about .10 carbon atoms soluble inthe, reaction mem and capable of: reactingwith the metal and .providthe conditions required forthe reduction. Whilethe ct mechanism of the reduction, is not clearlyunder- )d, the interactionof metal ..with acid m ay furnish :trons needed for thereduction or alternatively, the ibination of metal and acid may.furnish an :active 11 0f hydrogenwhich maybeinvolved in the reducl.
- the instant invention is also to be ,under- 2d,.to contemplate reduction of 2-di-substit-uted-aminohylpy-romeconic. acids directly in. solutions in which V are prepared.
- Example I 1 mixture of morpholine, 35 g., 37% aqueous formal- .yde, 32.0 g., and ethanol, 400 ml., is allowed to stand 15 minutes, then is stirred vigorously while pyromeic acid, 33.6 g., is added during '5 minutes.
- Example I p The procedure of Example I is repeated substituting for the zinc dust, stoichiometrically equivalent amounts of the .following metals: iron, aluminum, tin and magnesium. Substantially the same results are'obtained.
- Example 111 Arnixture of morpholine, '35 g., -37% aqueousformaldehyde, 32.0 g., and ethanol,3400 ml., is allowed to .stand for 15 minutes, then is stirred vigorously while pyromeconic acid, 33.6 g., is added during 5 minutes; the mixture is stirred for an additional .16' hours.
- pyromeconic acid 33.6 g.
- To this stirred suspension of Z-morpholinomethylpyromeconic .acid is; added 0.6 gram atoms of zinc metal dust, 500 m1. of waterand then 150 ml. of concentrated hydrochloric j acid is added at such a rate that thentemperature is maintained between 60 and 65 (3.; about 15 minutes are required.
- the mixture is, then stirred for an additional, 1.5 hoursat 65 C.; during thistime the reaction temperature is maintained by' external heating.
- the suspension is then heated to C. andis filtered while hot to remove unreacted zincmetal.
- the filtrate is cooled to 30 C., is
- the filtrate is the improvement which comprises treating the said 2-disubstituted-aminomethylpyromeconic acid Mannich base under reducing conditions with a metal-acid reducing agent combination.
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Description
pyromeconic acid, is obtained.
United States Patent M 3,171,842 PREPARATION OF GA PYRONES Bryce E. Tate, Niantic, Conn, assignor to Chas. Pfizer & Co., Inc, N ew York, N .Y., a corporation of Delaware No Drawing. Filed June 13, 1962, Ser. No. 202,102 Claims. (Cl. 260-3459) The present invention relates to a process for the preparation of gamma-pyrones. More particularly it is concerned With an improved process for the preparation of maltol, 3-hydroxy-2-methyl-4-pyrone, a particularly valuable gamma-pyrone, which is useful, among other things, for its flavor and aroma-enhancing properties.
While maltol is obtained commercially from wood, for example, by difficult and expensive extraction processes, it is known to the art that it can also be obtained by chemical syntheses from other gamma-pyrones. Thus the preparation of maltol from the freely-available and economical starting material, kojic acid, 2-hydroxymethyl-5- hydroxy-4-pyrone, is disclosed in the pending application of Bryce E. Tate and Robert L. Miller, Serial Number 171,732, filed February 7, 1962, now Patent No. 3,130,- 204, and assigned to the assignee of the instant application.
There is also known to the art another synthesis of maltol which is based on the disclosure of M. A. Spielman and M. Freifelder in volume 69, Journal of the American Chemical Society, pp. 2908-9 (1947). This synthesis is carried out in accordance with the following scheme:
pyromeconic acid The instant application is concerned with an improvement in the Spielman et al. process.
In the Spielman et al. article cited, it is disclosed that the yield in the step (1) in the reaction sequence is 43% and in step (2) the highest yield is reported to be 17%; thus an overall yield of maltol of only 7.3% based on It is noteworthy that after many experiments, this low yield was only obtained after conducting the reduction at a very high pressure (100 atmospheres) and in the presence of an expensive noble metal catalyst (palladium-on-charcoal).
It has now been found that application of improved processing conditions recently disclosed to the art by OBrien et al. in volume 25, Journal of Organic Chemistry, p. 86 (1960), to step (1) in the sequence and sub 3,171,84 Patented Mar. 2, 19d
Thus, application of the improvements of OBrien et a to increase the yield of Z-di-substituted aminomethylpyr meconic acid followed by application of the improv process of the instant invention to the maltol-formatir step allows the yield of maltol to be increased near four-fold to a cornercially-feasible level and permits su stantial savings in process and equipment costs.
It is accordingly a principal object of the present i vention to provide an improved means to obtain malt from readily available, economical gamma-pyrone sta: ing materials.
This and other objects obvious to those skilled in t' art may be readily achieved by application of the i1 proved process of the present invention which compris preparing maltol by treating a Z-di-substituted-amin methylpyromeconic acid with a metal-acid reducing age combination.
By the term 2-disubstituted-aminomethylpyromecor as employed herein and in the appended claims it is be understood that the present invention contemplat reaction products derived by treatment of pyromecor acid with formaldehyde and a secondary amine and 1mm to those skilled in the art as Mannich bases. In adt tion to the 2-piperidinomethylpyromeconic acid disclos by Spielman et al., a number of other Mannich bas may be used. Z-dimethylaminomethylpyromeconic ac: Z-di-n-butylamino-pyromeconic acid and 2-morpholin methylpyromeconic acid are examples of Z-di-su'ostitute aminomethylpyromeconic acids which are especially u: ful.
With respect to the term metal-acid reducing agent e01 binations as employed herein and in the appended chain it is meant, as is obvious to those skilled in the art, co] binations of acids with metals appropriately located the electromotive series of the elements, which combir tions provide a reducing action on organic compount As will be discussed in connection with the process, a. as will be exemplified in detail hereinafter, the ter metal-acid reducing agent combinations contemplated metals, for example, zinc, iron, aluminum, tin, magne um, and the like, and as acids, strong mineral acids su as, for example, hydrochloric acid and sulfuric acid, a monocarboxylic saturated open-chain aliphatic acids tl have from 1 to 10 carbon atoms and which are soluble the reaction system, such acid being represented by, t example, formic acid, acetic acid, isodecanoic acid, a the like.
The 2 di-substituted-arninomethylpyromeconic aci may be conveniently prepared by reaction of pyron conic acid with a mixture of formaldehydeand an orgar amine such as, for example, dimethylamine, di-n-but amine, piperidine, morpholine, and the like. Pyrorr conic acid may be obtained as is described in the Sa copending application, for example, by decarboxylati of comenic acid Which is in turn obtained by oxidation commercially-available kojic acid. The reaction C0111 tions suitable for formation of the Mannich base deriy from piperidine are described in the aforementiom Spielman et al. article. However, as has been mention hereinbefore, since higher yields are obtained, it is p1 ferred to employ the process of OBrien et al. substituti instead an equivalent amount of pyromeconic acid 1 the kojic acid employed therein. As will be exemplifi :s of water and other solvents such as lower alkanols,
tic acid, and the like; the mixture is treated with an aunt of metal such as, for example, zinc, iron, alumin, tin, magnesium, and the like, equivalent to from 111: 1.2 to about 2.5 gram atoms of metal per mole of nnich base; the resulting suspension is treated with the 1 member of the reducing agent combination .and 1:he ction mixture is maintained at a temperaturepf fr m ut to about 125 ;C.,.preferably, to minimize side ctions, from-about .25 toabout 75 ,C.,,and especially Eerably at about 5565 C., until paper chromatophic assay indicates .the 2-di-substitutedaminomethylomeconic .acid to have been substantially completely :s-umed. Maltol canbeisolated from-the-reaction mixa by adjusting thepI-I to from about ,1 tOgfilbOllt 3 and racting ,theacidic solution with about 5 volumes of organic solvent such as, for example, chloroform, er, benzene, and the like. Concentration of the oric layer causes crystallinemaltol to precipitate. This be removed byfiltration.
The metal to be employed .i-ntheimproved processrof present invention must'be appropriately located in electromotive series to react with the acid ,-1 nember ention may be any strong mineral acid or mono- I boxylicsaturated open-chain aliphatic acids of from a about .10 carbon atoms soluble inthe, reaction mem and capable of: reactingwith the metal and .providthe conditions required forthe reduction. Whilethe ct mechanism of the reduction, is not clearlyunder- )d, the interactionof metal ..with acid m ay furnish :trons needed for thereduction or alternatively, the ibination of metal and acid may.furnish an :active 11 0f hydrogenwhich maybeinvolved in the reducl. Among the ,mineral acids which are particularly ctive .are vhydrochloric,and sulfuric and among fthe anic acids which .are particularly efiective are formic acetic. It-is especially preferred to useeitherihydfouric acid or acetic acid in thisvreaction'since the ltol formed has a tendency to be...ob tai .nedin higher d and inhigher purity. )f course, the instant invention is also to be ,under- 2d,.to contemplate reduction of 2-di-substit-uted-aminohylpy-romeconic. acids directly in. solutions in which V are prepared. by treatment of pyromeconic acid with naldehyde; and an. amine. TIlnis the,metaliruly'v be ed to the-reaction mixture, thenthe. acid isfadded, and reduction is carried out as described hereinbeforeand :xemplifiedhereinafter. V The following examples are illustrativeof the process his invention. Example I 1 mixture of morpholine, 35 g., 37% aqueous formal- .yde, 32.0 g., and ethanol, 400 ml., is allowed to stand 15 minutes, then is stirred vigorously while pyromeic acid, 33.6 g., is added during '5 minutes. Stirring :ontinued for an additional ,16'hours and then the 4 reaction mixture is cooled in an ice bath and the product is collected by filtration. There is obtained an 84% yield of Z-morpholinomethylpyromeconic acid, M.P. 150151 C. An additional 8% yield of equally pure product is obtained afterlconcentration of the filtrate to about onefourth volume, cooling to 5 C. and collecting the crystals by filtration. The total yield of material is 92% of theory.
To a stirred suspension of 21.1 g. ofthe 2-morpholinomethylpyromeconic acid, zinc dust, 13 g., and Water, 180.
ml., is added 56 ml. of cone. hydrochloric acid at such a rate that the temperature is maintained between 60 and C.; about 15 minutes are required. The mixture is 7 then stirred for an additional 1.5 hours at 65 C.; during this time the reaction temperature is maintained by application ofan external heating bath as necessary. The suspension is then heated to 90 C. and is filtered while hot to remove unreacted zinc metal. cooled to 30 C. and is adjusted to pH 2 by the addition of 50% aqueous sodium hydroxide solution. The solution is extracted with one-fifth volume of chloroform 6 times and the chloroform layer is concentrated to one- .fourth volume and cooled. Crystalline maltol which precipitates is removed by filtration and weighs 4.44 g., 35% yield, l60.l6l C. Concentration of the filtrate to one-third volume yields ,an additional 2.23 g., 17.7% yield of maltol, M.P. l59 16l C. Atotal yield of 53% is obtained.
The procedure is repeated substituting for the morpholine, stoichiometrically equivalent amounts of the following bases: piperidine, dimethylamine and di-n-butylamine. Substantially'thesame results are obtained.
Example I] p The procedure of Example I is repeated substituting for the zinc dust, stoichiometrically equivalent amounts of the .following metals: iron, aluminum, tin and magnesium. Substantially the same results are'obtained.
Example 111 Arnixture of morpholine, '35 g., -37% aqueousformaldehyde, 32.0 g., and ethanol,3400 ml., is allowed to .stand for 15 minutes, then is stirred vigorously while pyromeconic acid, 33.6 g., is added during 5 minutes; the mixture is stirred for an additional .16' hours. To this stirred suspension of Z-morpholinomethylpyromeconic .acid is; added 0.6 gram atoms of zinc metal dust, 500 m1. of waterand then 150 ml. of concentrated hydrochloric j acid is added at such a rate that thentemperature is maintained between 60 and 65 (3.; about 15 minutes are required. The mixture is, then stirred for an additional, 1.5 hoursat 65 C.; during thistime the reaction temperature is maintained by' external heating. The suspension is then heated to C. andis filtered while hot to remove unreacted zincmetal. The filtrateis cooled to 30 C., is
adjusted to-pH 2 by the addition 'of 50% aqueous sodium hydroxide solution and the maltol isextracted by the procedure of Example I. Substantially the same results are obtained. 1
The procedure of Example IV'is illustrative of that,
,embodiment of the instant invention wherein the improved process is applied to the reaction mixture in which the Mannich base is prepared.
The filtrate is the improvement which comprises treating the said 2-disubstituted-aminomethylpyromeconic acid Mannich base under reducing conditions with a metal-acid reducing agent combination.
2. A process as in claim 1 wherein the said Z-di-substituted-aminomethylpyromeconic acid Mannich base is 2- morpholinomethylpyromeconic acid Mannich base.
8. A process as in claim 1 wherein the said 2-di-substituted-arninomethylpyromeconic acid Mannich base is 2- piperidinomethylpyromeconic acid Mannich base.
4. A process as in claim 1 wherein the said metal agent is Zinc and the said acid agent is hydrochloric acid.
5. A process as in claim 1 wherein the said metal age is zinc and the said acid agent is acetic acid.
References Cited in the file of this patent 5 Spielman et al.: Journal American Chemical Socie vol. 69, pp. 2908-2909 (1947).
OBrien et al.: Journal Organic Chemistry, vol. 2 pp. 86-89 (1960).
Campbell et al.: Journal Organic Chemistry, vol. I 10 pp. 221-226 (1950).
Fieser et al.: Advanced Organic Chemistry, page 11 Reinhold Publishing Corp., New York (1961).
Claims (1)
1. IN A PROCESS FOR THE REDUCTION OF 2-DI-SUBSTITUTEDAMINOMETHYL PYROMECONIC ACID MANNICH BASES TO MALTOL, THE IMPROVEMENT WHICH COMPRISES TREATING THE SAID 2-DISUBSTITUTED-AMINOMETHYLPYROMECONIC ACID MANNICH BASE UNDER REDUCING CONDITIONS WITH A METAL-ACID REDUCING AGENT COMBINATION.
Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IT2252762A IT1057851B (en) | 1961-11-21 | 1962-03-30 | PROCEDURE FOR THE PREPARATION OF PIPONI RANGE AND PRODUCTS SO OBTAINED |
US202102A US3171842A (en) | 1962-06-13 | 1962-06-13 | Preparation of gamma pyrones |
GB4322562A GB1033511A (en) | 1961-11-21 | 1962-11-15 | Gamma pyrones and preparation thereof |
DE19621518085 DE1518085B1 (en) | 1961-11-21 | 1962-11-20 | Process for the production of Matol |
NL727216463A NL151706B (en) | 1961-11-21 | 1972-12-05 | PROCESS FOR THE PREPARATION OF COMIC ACID. |
NL727216462A NL154738B (en) | 1961-11-21 | 1972-12-05 | PROCESS FOR PREPARING MALTOL. |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US202102A US3171842A (en) | 1962-06-13 | 1962-06-13 | Preparation of gamma pyrones |
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Publication Number | Publication Date |
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US3171842A true US3171842A (en) | 1965-03-02 |
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US202102A Expired - Lifetime US3171842A (en) | 1961-11-21 | 1962-06-13 | Preparation of gamma pyrones |
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US (1) | US3171842A (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3455960A (en) * | 1966-09-14 | 1969-07-15 | Monsanto Co | 4-pyrones |
US3501501A (en) * | 1969-02-14 | 1970-03-17 | Monsanto Co | Extraction of maltol |
-
1962
- 1962-06-13 US US202102A patent/US3171842A/en not_active Expired - Lifetime
Non-Patent Citations (1)
Title |
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None * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3455960A (en) * | 1966-09-14 | 1969-07-15 | Monsanto Co | 4-pyrones |
US3501501A (en) * | 1969-02-14 | 1970-03-17 | Monsanto Co | Extraction of maltol |
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