Note: Descriptions are shown in the official language in which they were submitted.
~ 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~
. ~ ,
: , , , , , .: : . ; , ~ ,. , - - ~ . . :,
- ~. ' ' :.: ~ : :. ;: ,.
086323
--2--
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
... . ", - . ~.. - .; `, . ..... .~ . .; .
; . - . ...
-. . ~ ; . ..
'' : ; ~;. ,: ,
'~' ' ~ ` ' '
10863Z3
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 $nventicn,
these compounds can be converted to intermediate 4 and
product 5 where R = CH20H or CH20-Alkyl~ Product S
(R = CH20H or CH20-Alkyl) can be converted to maltol as
described in United States 3,130,204 or Angew, ChemO. 81,
998 ~1969).
The following Examples are illustrative of
the proceæs of the invention and its use in the
production of y pyrones:
EXAMPLE 1
In a 3 neck-round:~okbom flask equipped with
a magnetic stirring bar, a jacketed addition funnel, a
. thermometer and a dry ice conden~or was added 22~4 g,
~002 mol) of intermedlate 1 ~R = CH3), 100 ml of
methanol and 2101 gO ~002 mol) of sodium carbonate, and
this mixture cooled to Q Co using an ice-acetone bathO
To this rapidly stirred solution was then added dropwise
a cold (-30) solution of ¢hlorine ~ 0 ml, 0024 mol~
in methanoI, The addition of chlorine was controlled
to keep the reaction temperature under 40C, The
addition required about 2 hours. After the addition,
the reaction mixture was stirred at ice ~ath temperature
for 30 minutes, an~ then allowed to warm to r~om
temperatureO The resu}ting slurry was filtered, the
methanol removed in vacuo ! the residue taken up in
benzene and passed through an alumina plug as a final
filterO Removal of the benzene prov$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
--7--
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)].
EXAMPLE 3
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
EXAMPLE 4
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.
EXAMPLE 5
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.
EXAMPLE 6
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
--8--
(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.
EXAMPLE 7
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.
EXAMPLE 8
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)~.
EXAMPLE 9
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)~
EXAMPLE 10
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.
EXAMPLE 11
The method of Example 8 may be repeated w~th
1086323
- 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
EXAMPLE 12
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.
EXAMPLE 13
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.
EXAMPLE 14
,,
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.
... . .
., :... -
,: ,
,: . .. . .
63Z3
--10--
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
EXAMPLE 16
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
EXAMPLE 17
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.
EXAMPLE 21
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).
EXAMPLE 22
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.
EXAMPLE 2 3
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
-12-
Substantially the same results are obtained ..
when boron trifluoride etherate is replaced with
p-toluenesulfonic acid, formic acid, zinc chloride
or tin tetrachloride.
- ., .... . - . .. . ..... .
.: . . ~.... - :
: : ' '~ '.. ,. ,.. .- :;; ,, ,,'., ,., ; ,.;.. ' , ,:
:
