CA1086323A - Process for the production of epoxy pyrones - Google Patents

Abstract

ABSTRACT
Epoxy pyrones of the formula wherein x is hydrogen, alkyl, aryl, alkenyl, aralkyl, -CH2OH or CH2O-Alkyl and R' is alkyl useful in the pro-duction of .gamma.-pyrone flavor, and aroma enhancers are obtained by treatment of .beta.-Pyrones of the formula

Description

~ 6323 The present Application is divided out of copending Application No 2559g3~ That invention relates to a process for preparing gamma-pyrones, for example maltol. Maltol i8 a naturally occurring substance found in the bark of young larch trees, pine needles and chicory. Early commercial production wa~ from the destructive distillation of wood. Synthesis of maltol from 3-hydroxy-2-~1-piperidylmethyl)-1,4-pyrone was reported by Spielman and Freifelder in J. Am. Chem.
-~ 10 Soc. 69, 2908 (1947). Schenck and Spielman, J. Am.
Chem~ Soc. 67, 2276 ~1945), obtained maltol ~y alkaline hydrolysis of streptomycin saLts. Chawla and McGonigal, J. Org. Chem. 39, 3281 119~4), and Lichtenthaler and ; Heidel, Angew, Chem. 81, 999 ~1969), reported the - 15 synthesis of maltol from protected carbohydrate derivatives.
Synthese~ of gamma-pyrones ~uch as pyromeconic acid, maltol, ethyl maltol and other 2-substituted-3--I hydroxy-gamma-pyrones are described in United States ` 20 Patents 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 product~. In addition, these "' 'I
materials are used as ingredient~ in perfume~ and es~ences. The 2-alkenylpyromeconio aoids reported in United States 3,644,635 and the 2-arylmethylpyromeconic acids described in United States 3,365,469 inhibit the -`~ growth of bacteria and fungi and are useful as flavor and aroma enhancers in foods and beverage~ and aroma ;:
` f~
. ~ , : , , , , , .: : . ; , ~ ,. , - - ~ . . :, - ~. ' ' :.: ~ : :. ;: ,.

enhancers in perfumes.
According to the present invention there is provided a process for preparing epoxy compounds of the formula:
~
I r R'O ~ O ~ X
wherein X 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:
~0 R'O ~ O ~ X
wherein X and Rl are as defined above, is treated in a water-containing medium with a base and hydrogen per-oxide. Such epoxy compounds are of use in the process of co-pending Application No. 255993.
From further aspects there are provided novel compounds of the formula:
., ~

R'O ~ ~ Q " ~`R*
wherein R* is ethyl and R' is lower alkyl of 1 to 6 carbon ~ atoms.
- 20 This invention permits the preparation of 2-substituted-3-hydroxy gamma-pyrones utilizing furfural as the starting material. Furfural is an inexpensive raw material which is prepared industrially from pentosans which are contained in cereal straws and brans.
As used throughout the specification and claim~, the term "lower alkyl" and the lower alkyl portion of alkoxy embraces both straight and branched ~ ' B

... . ", - . ~.. - .; `, . ..... .~ . .; .
; . - . ...
-. . ~ ; . ..

'' : ; ~;. ,: , '~' ' ~ ` ' ' chain alkyl radicals containing from one to ~ix carbon atoms; the term "lower alkenyl" embraces straight and branched chain alkenyl groups containing from two to six carbon atoms; the term "aryl" denotes a monocyclic aromatic hydrocarbon of six to eight carbon atom3; and the term "aralkyl" encompas~es lower alkyl groups in which aryl as defined above is substituted for a hydrogen atom.
The reaction scheme for producing ~ pyrones incorporting the present invention when starting from furfural i6 outlined as follows:

~ RN~X ~ ~ a or leotroly~L~

ORI

R'O~ \ ~
: F

~ H+
:;` ~'4' ~ OH ~ O R' R R' o~ol 2 2 15 Intermediates: R' = Cl 6 alkyl R = hydrogen, allyl~ aryl! alkenyl, aralkyl :~

, .- .

; ~
": ' 1t)863;~3 Final Product ~5): R=hydrogen, alkyl, alkenyl, aryl, aralkyl R=H, pyromeconic acid R=CH3, maltol R=CH2CH3, ethyl maltol The reaction of furfural with the appropriate Grignard reagent iB described in Chemioal Abstracts 44, 1092d (1949).
The preparation of intermeaiate 2 ~R = H) by electrolysis in methanol i8 described in United States

2,714,576 and Acta. ChemO Scand. 6, 545 ~1952). The synthe~is employing bromine in methanol is r-ported in Ann. 516, 231 (1935). The general concept of using chlorine in an alcoholic ~olvent i~ al80 well known 15 ~for example, British Patent 595,041). It has been found during the process of this invention that the reaction of intermediate 1 with chlorine in an alcoholic solvent at a temperature between -70 and ;
50C. gives a clean conversion to the desired intermediates 2 with the HC1 by-product being neutralized by a base such as ammonia, sodium carbonate or other alkali metal basesO Although the early literature involving thi~ reaction cites yields of up ~- t~ around 50% the proce~s of the present invention results in yields in exce~s of 90%.
Intermediate 2 tR = CH3) is de~cribed in Acta.
Chem. Scand. 9, 17 ~1955); and Tetrahedron 27, 1973 (1971). Intermediate 2 ~R - CH2CH3) is a new compound which can be made by me*hods already describedO
The treatment of intermediate 2 with a ~trong organic acid is novel and it produces the de~ired 6-alkoxy derivative 3 directly in high yield and avQids the formation of the corre~ponding hydroxy derivative which i~ very unstable to further roactions. Inter-: 35 mediate 2 iB contacted with an acia which is preferably es~entially anhydrous, although the presence of a protic solvent such as an alcohol or a small amount of : -- . ; : ; . , 1~iB63Z3 water ~s actually beneficial. Following this treatment, the product in a state of purity suitable for con-version 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 or below will convert intermediate 2 to the desired intermediate 30 Other suitable organic acids include p-toluenesulfonic acid, methanesulfonic acid, citric acid, oxalic acid and chloroacetic acid; suitable mineral acidæ include sulfuric acid, hydrochloric acid and phosphoric acidO
Acidic resins such as Amberlite GC-120 and Dowex 50W
may also be employed. ~"Amberlite" and "Dowex" are Trademark3) The epoxidation of intermediate ~ to the epoxy ketone 4 is a new and novel process and ~ the subject of this applicationO Intermediate 3 is dissolved in a suitable golvent ~uch as water or an alcohol such as isopropyl alcohol or methanolO A base such as sodium bicarbonate or sodium hydroxide i~
added followed by the addition of H202~30~o The desired intermediate 4 can be separated by conventional extraction techniques, and is suitable for rearrangement to the desired pyrone 5 without further purificationO
The final rearrangements of the epoxy ketones 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 desired gan~a-pyrone 5 i8 effected by conventional crystallization or extraction techniques, The pure gamma-pyrone may be recry6tallized from an appropriate solvent such as isopropanol, methanol or water. Al~hough hot aqueoug mineral acid such as sulfuric or hydrochloric acid i~
the most convenient method of converting intermediate 4 to product 5, the desired gamma-pyrone can be produced by Lewis acids such as borontrifluoride etherate, zinc chloride and tin tetrachloride; by acidic ion resins .~ , .~ .:., 1~363Z3 such as Amberlite GC-120 or Dowex 50W; and by strong organic acids such as p-~oluenesulfonic acid or formic acidO
Compounds related to intermediate 3 ~R = CH~OH
or R = CH20-Alkyl) can be prepared from carbohydrate sources as described in Account~ of Chemical Research 8, 192 ~1975). By the procQss of the present $nventicn, these compounds can be converted to intermediate 4 and product 5 where R = CH20H or CH20-Alkyl~ Product S
(R = CH20H or CH20-Alkyl) can be converted to maltol as described in United States 3,130,204 or Angew, ChemO. 81, 998 ~1969).
The following Examples are illustrative of the proceæs of the invention and its use in the production of y pyrones:

In a 3 neck-round:~okbom flask equipped with a magnetic stirring bar, a jacketed addition funnel, a . thermometer and a dry ice conden~or was added 22~4 g, ~002 mol) of intermedlate 1 ~R = CH3), 100 ml of methanol and 2101 gO ~002 mol) of sodium carbonate, and this mixture cooled to Q Co using an ice-acetone bathO
To this rapidly stirred solution was then added dropwise a cold (-30) solution of ¢hlorine ~ 0 ml, 0024 mol~
in methanoI, The addition of chlorine was controlled to keep the reaction temperature under 40C, The addition required about 2 hours. After the addition, the reaction mixture was stirred at ice ~ath temperature for 30 minutes, an~ then allowed to warm to r~om temperatureO The resu}ting slurry was filtered, the methanol removed in vacuo ! the residue taken up in benzene and passed through an alumina plug as a final filterO Removal of the benzene prov$ded 31~9 gO ~91~) of the deslred dimethoxy dihydrofuran 2 ~R - CH3, R'= CH3). This material can be used without further purification or it can be distil-led, b~po 76-78/5mm [104-1~7~/10-llmm, Acta Chem. ScandO 9,17 tl955~]o : .

10~6323 Analysis:
Calc'd. for C8H1404: C, 55.22 H, 8.11 Found:C, 55.34 H, 8.04 EXAMP~E 2 The method of Example 1 was repeated wlth intermediate 1 (R = H) to yield intermediate 2 ~R z H, R' = CH3), b.p. 8Q-82/Smm [71/l.Omm Tetrahedron 27, 1973 ~1971)].

The method of Example 1 was repeated with intermediate 1 (R = H~ to yield intermediate 2 ~R s H, R' = CH3) b.p. 102/lOmm.
Analy~is:
; Calc'd. for C9H1604: C, 57.50 H~ 8-58 - 15 Found:C, 57.39 H, 8.59 The method of Example 1 was repeated UB ing ~ intermediate 1 (R = CH3) replacing metha~ol with ii i80propanol 2 [R = CH3, R' = CH~CH3)2~, b.p. 62-64/-- 20 0005 mm.

The method of Example 1 may ~e repeated using bromine instead of chlorine using in~ermediate 1 to yield intermediate 2 where R is hydrogen, methyl, ethyl, hexyl, phenyl, vinyl, l-butenyl, allyl and l-hexenyl; and R' i~
methyl, ethyl, isopropyl and hexyl.

In a small glass electroly~is vessel having a carbon anode and nickel cathode was placed 50 ml of methanol, 0.5 ml of concentrated sulfuric acid, and 1.12 g. ~0.01 mol) of the intermediate 2 ~R = CH3, R' =
CH3)and th~ solution cooled to -20C. An electrolysis was then carried out using a potentiostat/galvanostat Princeton Applied ~esearch Corpcration Model 373 instrument Bet to deliver a constant current of 0.6 amperes. After a reaction time of 30 minutes, the reaction was poured into water and the product 3 .. . . : .:................ . i :...... .

. ~ ' "
..

~ . ,. :~ .

10~363Z3 (R = CH3, R' = CH3), isolated by a chloroform extraction procedure. This procedure iB ~imilar to that described in United States 2,714,576 with sulfuric acid replacing ammonium bromide as the electrolyte.

The method of Example 6 may be repeated with intermediate 2 to yield intermediate 3 where R iB
hydrogen, ethyl, hexyl, phenyl, benzyl, vinyl, allyl, l-butenyl and l-hexenyl and R' is ethyl, isopropyl and hexyl.

To a 2-liter, 3-neck n~d bottcm flask equipped with a magnetic stirrer, dropping funnel and a thermometer was adde~ 400 ml of formic acid and 20 ml of methanol. To this solution was added a solution of intermediate 2 (R = CH3, R' = CH3) 104-4 goj3,6 ~ol ln -40 ml of methanol. The dropwise addition required 15 minutesO The reacti~n was poured in a liter of water and extracted 3 times with 500 ml portions of chloroform.
The combined chloroform washings were washed with a sodium bicarbonate aqueous solution and with hrineO The chloroform solution was evaporated to a crude yield of 76 g (89%) of in~ermediate 3 ~R = CH3, R' = CH3) as a l$ght brown product. ~he crude material may be used as such or distilled at 2mm pressure, 50-52C. [82-85/-30mm, Tetrahedron 27~ 1973 ~1971)~.

The method of Example 8 was repeated wlth analogous intermediate 2 ~R z H, R' = CH3) to yield intermediate 3 ~R = H, R' = CH3) b.p. 60-66/14mm [76-81/23mm, Tetrahedron 27, 1973 ~1971)~

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

The method of Example 8 may be repeated w~th - intermediate 2 to yield intermediate 3 where R is hexyl, phenyl, benzyl, vinyl, allyl, l-butenyl and l-hexenyl;
and R is isopropyl and hexylO

The method of Example 8 may be repea~ed, with comparable results, replacing formic acid with an organic selected from the group consisting of citric acid, oxalic acid, chloroacetic acid, p-toluenesulfonic acid, methansulfonic acid and trifluoracetic acid.

In a 3-neck roundbcktcm 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 = C~3, R' - CH3) in diethyl ether (10 ml) and the solution was cooled to -40Co To this solution was then added dropwise 1.6 ml of concentrated sulfuric acid and the black mixture stirred for 5 minutes at -40Co ~ poured into water and the desired - intermediate 3 (R z CH3, R' = CH3) isolated by the ; 20 method of Example 8.
Substantially the sam~ results may be obtained replacing sulfuric acid with hydrochloric or phosphoric acids.

,, To a dry flask was adde~ 1.05 gram~ ~0.0074-mol) of interme~iate 3 ~R z C~3, R' - CH30) dissolved in 20 ml of isopropyl alcohol and the flask cooled to 0C
Then 0.5 g. (0.0059 mol) of sodium bicarbonate and 2.0 ml (0.023 mol) of 30% hydrogen peroxide were added~
and the reaction allowed to stir at room temp~rature for about 2 hours. The reaotion mixture was 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 analytic sample was purified by gas chromatography.

... . .
., :... -,: , ,: . .. . .

Analys i8:
Calc~d. for C7H1004: C, 53016 ~ 6037 Found:C, 52090 H, 6 27 ~XAMPLE 15 The method of Example 14 was repeated with intermediate 3 ~R = H, R' = CH3) to yield intermediate 4 ~R = H, R' = CH3).
Analyeis:
Calc'd for C6H804: C, 50000 ~ 5~59 13 Found:C, 50009 ~, 5081 The method of Example 14 wae repeated with intermediate 3 (R = CH2CH3, R' = CH3) to yield inter-mediate 4 (R = CH2CH3' R' = CH3)-Analysis:
Calcid for C8H1204: C, 55.81 H, 7.02 Found:C, 55 95 H, 7.04 The method of Example 14 may be repeated with intermediate 3 to yield intermediate 4 where R iB hexyl, phenyl, benzyl, vinyI, allyl, l-butenyl and l-hexenyl;
and R' is ieopropyl and hexyl.
EXAMP~E 18 To a 75 ml flask was added 2.84 g. ~OoG2 mol) of intermediate 3 ~R = CH3, R' = CH3), 10 ml of water and 10 ml of isopropanol. The solution was cooled to 0-5Co~ and the pH adjusted to 700-9.0 with 1 N NaOHO
Then 201 ml-of 30% hydrogen peroxide was added dropwise, with NaOH also added ae neceesary to maintain conetant pH. Cooling was necessary to keep the pot temperature below 10Co After the~addition of peroxide, the reaction was stirred at 8-10C. for about one hour, poured in water and the solution extracted with chloroform.
Solvent removal yielded 2099 g. ~94.5~) of the inter-mediate 4 (R = C~3, R' = CH3) ae a clear oil. Reactisntemperature above 15C. and a pH above 9~5 ox bèlow 605 re~ult in lower yields of intermediate 4.

..
.
, - . - :, , . ; - :
. : : .
.

;323 Substantially the same results are obtained replacing isopropanol with water.
EXAMP~E 19 To a flask with a conden~er was added 3.7 g~
5 ~0~ 023 mol) of intermediate 4 ~R e CH3, R' - CH3~ and 50 ml of 2M H2S04 After heating this two phase solution for 1~5 hours at reflux, the reaction mixture was cooled, adju~ted tc pH 2.2 with 6 N NaOH, extracted ~3 times with 100 ml volumes of ohloroform and the : 10 combined solvent extract concentrated to yield product 5 ~R = CH3, maltol).
EX~MP~E 20 The method of Example 19 may be repeated with intermedia~e 4 where R is hydrogen, ethyl, hexyl,phenyl, 15 benzyl, allyl, vinyl, l-butenyl and l-hexenyl; and R' i~
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 pres6ure bottle WaB
' added 3.16 g. ~0.02 mol) of intermediate 4 ~R = CH3, R' = CH3) and 50 cc of 2 M H2S04 The vess~l was sealed and heated to 140-16~ for 1-2 hoursr After ; cooling, the reaction was proceesed as in Example 19 25 to yield maltol (R = CH3).

The method of Example 19 and 20 may be repeated, with comparable results, r~placing suluric acid with hydrochloric acid, Dowex 50W and Amberl~te 30 GC-120.

To a small flask was added 1. 58 g. ~0~01 mol) of intermediate 4 (R = CH3, R' = CH3) an~ 25 ml of benzene followed by 3.7 ml of boron trifluoride etherate.
35 After stirring for 24 hours at 25Co ~ the solvent was removed, the residue extracted with chloroform, and the chloroform removed to yield maltol ~R = CH3).

- : . . , -. . . . :: ,: .:., - , , -;' :. ' . : ' :. . :- , !

' ' ' ~ ' ': : ~ :, ' 108~ Z3 Substantially the same results are obtained ..
when boron trifluoride etherate is replaced with p-toluenesulfonic acid, formic acid, zinc chloride or tin tetrachloride.

- ., .... . - . .. . ..... .

.: . . ~.... - :
: : ' '~ '.. ,. ,.. .- :;; ,, ,,'., ,., ; ,.;.. ' , ,:

:

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 compounds of the formula:

wherein X 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:

in a water-containing medium is treated with base and hydrogen peroxide.

2. A process according to claim 1, wherein the com-pound:

is dissolved in water, isopropyl alcohol or methanol and is successively mixed with a base and aqueous hydrogen peroxide.

3. A compound of the formula:

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