CA1089865A - PROCESS FOR THE PRODUCTION OF .beta. PYRONES - Google Patents

Abstract

ABSTRACT
.beta.-Pyrones of the formula wherein R' is alkyl and R is hydrogen, alkyl, aryl, alkenyl or aralkyl, useful as intermediates in the production of .gamma.-pyrone flavor and aroma enhancers are obtained by reaction of a compound of the formula

Description

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The present application i8 divided out of eopending Application No. 255993. That application relates to a process for preparing gamma-pyrones, for example maltol. Maltol is a naturally occurring ~ubstance found in the bark of young larch trees, pine needles and chicory. Early commercial production was from the destructive distillation of wood.
Synthesis of maltel from 3-hydroxy-2-~1-piperidylmethyl)-1,4-pyrone was reported by Spielman and Freifelder in J. Am. Chem. Soc. 69, 2908 ~1947). Schenck and Spielman, J. Am. Chem. Soc. 67, 2276 ~1945), obtained maltol by alkaline hydrQlysi~ of streptomyein salts. Chawla and McGonigal, J. Org. Chom. 39, 3281 ~1974), and Liehtenthaler and Heidel, Angew, Chem. 81, 999 ~1969), reported the ~ynthesi~ of maltol from proteeted earbohydrate derivatives.
Synth-~es of gamma-pyrone~ ~u¢h as pyromeconic acid, maltol, ethyl maltol and other 2-sub~tituted ~3-hydroxy-gamma-pyrone~ are de~cribed in United States P-tentg 3,130,204, 3,133,089, 3,140,239, 3,159,652, 3,376,317, 3,468,915, 3,440,183 and 3,446,629.
Maltol and ethyl maltol enhance the flavor and aroma of a variety of food produets. In addition, th-se materials are used a~ ingred ients in perfumes and ~enees. The 2-alkenylpyromeeonie acids reported in United States 3,644,635 and the 2-arylmethylpyromeconie aeids described in Unitea Stat-~ 3,365,469 inhibit the growth of ba¢teria and fungi and are useful a6 flavor and aroma enhancers in foods and beverage6 and aroma :

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`` 10898~5 enhancers in perfumes.
According to the pre~ent invention there is provided a process for preparing ~-pyrones useful in the production of y pyrones according to the process of Application No. 255993, said ~-pyrones havlng the formula:

R'O ~R
wherein R is hydrogen, lower alkyl of 1 to 6 carbon atoms, lower alkenyl of 2 to 6 carbon atoms, phenyl or benzyl and R' is lower alkyl of 1-6 carbon atoms wherein a compound of the formula ~ OR~
R'O ~ ~ ~~
~ R
~- wherein R and R' are as defined above i8 treated with a substantially anhydrous acid of pKa 4 or below.
From a further aspect there are provided novel compounds of the formula ~ and wherein R i~ ethyl and R' is lower alkyl of 1 to 6 carbon atoms. Such compounds are intermediate~ in the production of ethyl maltol which as described in U.S.
Patent 3376317 has aroma and flavor enhancing properties superior to those of maltol, This invention permits the preparation~of 2-sub~tituted-3-hydroxy gamma-pyrones utilizing furfural as the starting material. Furfural is an inexpensive raw material which i~ prepared industrially from .

.
- ~ ' ' `` 1(~9~5 pentosans which are contained in cereal straws and brans.
As used throughout the specification and claims, the term n lower alkyl" and the lower alkyl portion of alkoxy embraces both straight and branched chain alkyl radicals containing from one to ~ix carbon atoms; the term "lower alkenyl" em~races straight and branched chain alkenyl groups containing from two to 8iX carbon atoms; the term "aryl denotes a monocyclic aromatic hydrocarbon of 8iX to eight carbon atom~; and the term "aralkyl" encompa8ses lower alkyl groups in which aryl as defined above is substituted for a hydrogen atom.
The reaction scheme for producing y-pyrones incorporting the present invention when starting from furfural is outlined as follows:

aX~ ~H or electrolys~s ~=~R ' R ' O~HOH

[~ ~H20 ~ H20 o/~ H202 R ' Intermediates: R ' = Cl 6 alkyl R = hydrogen, allyl, aryl, alkenyl, aralkyl Final Product ~5): R~hydrogen, alkyl, alkenyl, aryl, aralkyl R-H, pyromeconic acid R-CH3, maltol R=CH2CH3, ethyl maltol .. . . .
- . ~ . . .. : - , , -. . . ,, .. ' ' ', ~ ~ . - ' .- :
. .
~' '' : . ' ' . ~ .-.

~ 3~ ~ 5 The reaction of furfural with the appropriate Grignard reagent is described in Chemical Abstracts 44, 1092d ~1949).
The preparation of intermediate 2 tR = H) by electrolysis in methanol i8 described in United State~

2,714,576 and Acta. Chem. Scand. 6, 545 ~1952). The synthesi~ employing bromine in methanol iB reported in Ann. 516, 231 (1935). The general concept of u~ing chlorine in an alcoholic solvQnt is also well known (for example, British Patent 595,041). It has been found during the process of this invention that the reaction of intermediato 1 with chlorine in an alcoholic solvent at a temperature between -70 and 50C. gives a clean conversion to the desired intermediate 2 with the HCl by-product being neutralized by a base such as ammonia, sodium carbonate or other alkali metal bases.
Although the early literature involving this reaction cites yields of up to around 50% the process of the pre~ent invention results in yields in excess of 90%.
Intermediate 2 ~R - CH3) iB described in Acta. Chem. Scand. 9, 17 ~1955); and Tetrahedron 27, 1973 ~1971). Intermediate 2 ~R - CH2CH3) is a new compound wh~ch can bo made by methods already d-scribed.
Tho treatment of intormediate 2 with a strong acid is novel and constitute~ the present invention. It produces the desired 6-alkoxy derivative 3 directly in high yield and avoids the formation of tho corresponding hydroxy derivative which iB very unstable to further reactions. Intermediate 2 i~ contacted with an acid which iB preferably ossentially anhydrous, although the presence of a protic solvont such a~ an alcohol or a small amount ef water is actually beneficial.
Following this treatment, the product in a state of purity suitable for conversion to intermediate 3, is separated from the acid medium by conventional extraction techniques. Although formic and trifluoracetic acids are preferred, any acid with a pKa of approximately 4 -`` 10t~ 5 or below will convert intermediate 2 to the desired intermediate 3. Other suitable organic acids include p-toluenesulfonic acid, methanesulfonic acid, citric acid, oxalic acid and chloroacetic acid; suitable mineral acids inc~ude sulfuric acid, hydrochloric acid and phosphoric acid. Acidic resins such as Amberlite GC-120 and Dowex SOW may also be employed. ~"Amberlite"
and "Dowex" are Trademarks).
The epoxidation of intermediate 3 to the epoxy ketone 4 is a new and novel process. Intermediate 3 is dis~olved in a suitable solvent such as water or an alcohol such as isopropyl alcohol or methanol. A base such as sodium bicarbonate or sodium hydroxide is added followed by the addition of H202~30%). The desired intermediate 4 can be separated by conventional extraction techniquQs, and ig suitable for rearrangement to the desired pyrone 5 without further purification.
The final rearrangements of the epoxy ~etones 4 to gamma-pyrones 5 are novel and proceed in good yield and purity. The intermediate 4 is reacted in an acid medium and subsequent isolation of the dQsired gamma-pyrone 5 is effected by conventional cry6-tallization or extraction techniques. The pure gamma-pyrone may be recry~tallized from an appropriate solvent such as i~opropanol, methanol or water. Although hot aqueous mineral acid such as sulfuric or hydrochloric acid is the mo~t convenient method of converting inter-mediato 4 to product 5, the desired gamma-pyron~ can be produced by Lewis acids such as borontrifluoride etherate, zinc chloride and tin tetrachloride; by acidic ion resins such as Amberlite GC-120 or Dowex 50W; and by strong organic acids such as p-toluenesulfonic acid or formic acid.
Compounds related to intermediate 3 (R = CH20H
or R = CH20-Al~yl) can be prepared from carbohydrate souroes as described in A~x~nts of Chemical R~x~h 8, 192 ~1975) : ~, '' ' : ~

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By the process of the present invention, the6e compounde can be converted to intermediate 4 and product 5 where R = CH20H or CH20-Alkyl. Product 5 ~R s CH20H or CH20-Alkyl) can be converted to maltol as de~cribed in United State~ 3,130,204 or Angew. Chem. 81, 998 ~1969).
The following Examples are illu6trative of the process of the invention and its use in the production of y_pyrones.

10In a 3 neck-ro~ botbom flask equipped with a magnetic stirring bar, a jacketed addition funnel, a thermometer and a dry ice condensor was addod 22.4 g.
(0.2 mol) of intermediate 1 ~R ~ CH3), 100 ml of methanol and 21.1 g (0.2 mol) of sodium ¢arbonate, and this mixture cooled ~o 0C. using an ic~-acetono bath. To thi~ rapidly ~tirred solution was th-n added dropwise a cold ~-30) solution of chlorine ~11.0 ml, 0.24 mol) in methanol. The addition of chlorine wa~ ¢ontrolled to keep the reaction temperature under 40C. The addition required about 2 hours. Aft-r the addition, the reaction mixture was stirred at ice bath temperature for 30 minutes, and then allowed to warm to room temperature.
Th- rQsulting ~lurry was filtered, the methanol removed in vacuo, the re~idue taken up in benz~ne and pa~sea through an alumina plug a~ a final filter.
Removal of the benzene provided 31.9 g. ~914) of the de~ired dimethoxy dihydrofuran 2 lR ~ C~3, R'- CH3).
Thi~ matorial can be u~ed without further purification or it can be distilled, b.p, 76-7B/5mm ~104-107/10-llmm, Acta Chem. Scand. 9, 17 ~1955)~.
Analy~
Calc'd. for C8H1404: C, 55.22 H, 8.11 Found:C, 55.34 H, 8.04 EXAMP~E 2 35 The method o~ Exampl- 1 wa~ rep-ated with intermediate 1 ~R s H) to yield intermediate 2 ~R = H, R' = CH3), b.p. 80-82/5mm [71/l.Omm TQtrah-dron ,: . .

10~ 5 27, 1973 (1971)1 The method of Example 1 wa~ repeated with intermediate 1 (R = H) to yield intermediate 2 ~R = H, R' = CH3) b p 102/lOmm Analysis Calc'd for CgH1604 C, 57 50 ~, 8 58 FoundC, 57 39 H, 8 59 The method of Example 1 was repeated using intermediate 1 (R = CH3) replacing methanol with isopropanol 2 [R = CH3, R' ~ C~CH3)2~, b p 62-64/-0 05 mm ~ EXAMPLE 5 The method of Example 1 may b- repeated using bromine in~tead of chlorine uslng intermediate 1 to yleld intermediate 2 where R is hydrogen, methyl, ethyl, hexyl, phenyl, vinyl, l-butenyl, allyl and l-hexonyl;
and R' i8 methyl, ethyl, isopropyl and hexyl In a ~mall glaJ~ electroly~i~ ve~sel having a carbon anode and nickel cathode was plaoed 50 ml of methanol, 0 5 ml of concontrat-d ~ulfuric acid, and 1 12 g ~0 01 mol) of the interm diat- 2 ~R ~ CH3, R' - CH3) and the 801ution cooled to -20C An 6 electroly~is was then carried out u~ing a potontio~tat/-galvanostat Princeton Appli-d R-~-arch Corporation Model 373 in~trument set to doliv-r con~tant current of O 6 amperes After a reaction time of 30 minut-s, tho reaction wa~ poured into water and th- product 3 ~R - CH3, R' = CH3), i~olatod ~y a chloroform extraction procedure This procedure is imllar to that de~cribod in Unitod States 2,714,576 with ~ulfuric acid replacing ammonium ~romido as the electrolyte EXAMP~E 7 Ths method of Example 6 may be repeat-d with interm diate 2 to yiold ~nterm-diat- 3 whore R 1B

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hydrogen, ethyl, hexyl, phenyl, benzyl, vinyl, allyl, l-butenyl and l-hexenyl and R' i~ ethyl, isopropyl and hexyl.

~o a 2-liter, 3-neck round ~ttom flask equipped with a magnetic stirrer, dropping funnel and a thermometer was added 400 ml of formic acid and 20 ml of methanol. To thi~ solution was added a solution of intermediate 2 (R = C~3, R' = C~3) 104.4 g., 06 mol in 40 ml of methanol. The dropwise addition required 15 minutes. The reaction was poured in a liter of water and extracted 3 times with 500 ml portions of chloroform.
The combined chloroform wa~hings wore washed with a sodium bicarbonate aqueou~ ~olution and with brine.
The chloroform solution was evaporated to a crude yield of 76 g ~89%) of intermediato 3 ~R - CH3, R' ~ CH3) as a light brown product. The crude material may be used as such or distilled at 2mm pressure, 50-52C. ~82-85/-30mm, Tetrahedron 27, 1973 ~1971)].

The mothod of Example 8 was repeated with analogous intermediate 2 ~R ~ H, R' - C~3) to yield intermediate 3 ~R - H, R' - CH3), b.p. 60-66/14mm t76-81/23mm, Totrahedron 27, 1973 ~1971)1.

-The method of Example 8 was repeated with intermodiate 2 ~R = CH2CH3, R' - CH3) to yield inter-mediate 3 ~R = CH2CH3, R' - CH3), b.p. 79-80/14mm.

The method of Examplo 8 may be repeated with intermediate 2 to yield intermediat- 3 where R iB hexyl, phenyl, benzyl, vinyl, allyl, l-butenyl and l-hexenyl;
and R i8 iBopropyl and h-xyl.

The mothod of Example 8 may be repeated, with comparable result~, replacing formi¢ acid w~th an organic selected from the group consisting of citric acid, oxalic ~' , ''` ' : ' , .

s acid, chloroacetic acid, p-toluenesulfonic acid, methan-sulfonic acid and trifluoracetic acid.

In a 3-neck ~ bot~om equipped with an addition funnel, low temperature thermometer and stirring bar was prepared a solution of 5.0 g~ ~0~029 mol) of intermediate 2 (R = CH3, R' ~ CH3) in diethyl ether (10 ml~ and the solution was cooled to -40C~ To thi6 solution was then added drop-wise 1.6 ml of concentrated sulfuric acid and the black mixture Qtirred for 5 minutes at -40C~, poured into water and the desired inter-mediate 3 ~R = CH3, R' = CH3) isolated by the method of Example 8.
Substantially the same result~ may be obtained replacing sulfuric acid with hydrochloric or phosphoric acids.

To a dry flask was added 1.05 grams ~0.0074 mol) of intermediate 3 ~R e CH3, R' - CH30) diesolved in 20 ml of isopropyl alcohol and the flask cooled to 0C.
Then 0.5 gO ~000059 mol) of 60dium bicarbonate and 2.0 ml ~OD 023 mol) of 30% hydrogon peroxide were added, and the reaction allowed to stir at room temperature for about 2 hoursO The reaction mixture wa~ poured into 100 ml of water and the water extracted with chloroform, followed by concentration to yield oil which could be distilled at 70-90/3mm. An analytio sampl- wa~
purified by gas chromatography.
Analyeis:
30 Calc d- for C7 104 Found: C, 52.90 H, 6.27 The method of Example 14 was repeated with intermediate 3 (R = H, R' ~ CH3) to yield intermediate 35 4 (R - H, R' = CH3).
Analysis:
Calc d for C6H804: C, 50.0 Found: C, 50.09 H, 5.81 ~ . . . . . . . .. .. . .
., , . . . .. . ,-- . - . ~ - -, . . - - .
- - .
. - , ,.
: ., - ~ , . . . .

.~0~ ;5 The method of Example 14 was repeated with intermediate 3 (R = CH2CH3, R' = C~3) to yield inter-mediate 4 (R = CH2CH3, R' = CH3).
Analysis:
Calc d for C8H124 C, Found: C, 55.95 H, 7.04 The method of Example 14 may be repeated with intermediate 3 to yield intermediate 4 where R is hexyl, phenyl, benzyl, vinyl, allyl, l-butenyl and l-hexenyl;
and R' is isopropyl and hexyl.

To a 75 ml flask was added 2.84 g. (0.02 mol) of intermediate 3 (R = CH3, R' ~ CH3), 10 ml of water and 10 ml of isopropanQl. The solution was cooled to 0-5C., and the pH adjusted to 7.0-9.0 with 1 N NaOH.
Then 2.1 ml of 30% hydrogen peroxide was added dropwise, with NaOH also added as necessary to maintain constant pH. Cooling was necessary to keep the pot temperature below 10C. After the addition of peroxide, the roaction was stirred at 8-10C. for about one hour, poured in water and the solution extracted with chloroform Solvent removal yielded 2.99 g. (94.5%) of the intermediate 4 ~R z CH3, R' = CH3) as a clear oil. Reaction temperature above 15C. and a p~ above 9.5 or below 6.5 result in lower yields of intermediate 4.
Substantially the same results are obtained replacing i~opropanol with water.

To a flask with a condenser was added 3.7 g.
(0.023 mol) of intermediate 4 ~R - CH3, R' - CH3) and 50 ml of 2M H2S04. After heating this two phase ~olution for 1.5 hours at reflux, the reaction mixture was cooled, adjusted to pH 2.2 with 6 N NaOH, extracted

3 times with 100 ml volumes of chloroform and the combined solvent extract concentrated to yield product ' -' ' ' ~

10~98~;5 5 ~R = CH3, maltol) The method of Example 19 may be repeated with intermediate 4 where R is hydrogen, ethyl, hexyl, phenyl, benzyl, allyl, vinyl, l-butenyl and l-hexenyl; and R' i8 methyl, ethyl, isopropyl and hexyl to yield product 5 where R is hydrogen, ethyl, hexyl, phenyl, benzyl, allyl, vinyl, l-butenyl and l-hexenyl To a 250 cc Wheaton presure bottle was added 3 16 g (0 02 mol) of intermediate 4 ~R ~ C~3, R' = C~3) and 50 cc of 2 M H2SO4 The vessel was sealed and heated to 140-160 for 1-2 hours After cooling, the reaction was processed a~ in Example 19 to yield maltol (R - CH3) The method of Example 19 and 20 may be repeated, with comparable results, replacing sulfuric acid with hydrochloric acid, Dowex 50W and Amberlite GC-1200 To a small flask was added 1~ 58 gO ~0 01 mol) of intermediate 4 (R = C~3, R' D CH3) and 25 ml of benzen- followed by 307 ml of boron trifluoride etherate After stirring for 24 hour~ at 25Co~ the solv-nt was removed, the residue extracted with chloroform, and the chloroform removed to yield maltol ~R ~ C~3)o Substantially tho ~ame result~ are obtained wh-n boron trifluoride eth-r~te is replaced with p-toluenesulfonic acid, formic acid, zinc chloride or tin tetrachloride ,. - . . - .- - '' ~: . ' -,....... - - -....... - ~. .. . . . .
.
.
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Claims (3)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for the production of a compound of the formula:

wherein a compound of the formula wherein R is hydrogen, lower alkyl of 1 to 6 carbon atoms, lower alkenyl of 2 to 6 carbon atoms, phenyl or benzyl and R' is lower alkyl of 1-6 carbon atoms is treated with a substantially strong anhydrous acid of pKa 4 or below.

2. A process according to claim 1, wherein the acid employed is formic acid, trifluoroacetic acid, p-toluene sulfonic acid, methane sulfonic acid, citric acid, oxalic acid or chloroacetic acid.

3. A compound of the formula:

wherein R* is ethyl and R' is lower alkyl of 1 to 6 carbon atoms.