CA1117541A - 4-halo-dihydropyrans and the preparation thereof - Google Patents
4-halo-dihydropyrans and the preparation thereofInfo
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- CA1117541A CA1117541A CA000363274A CA363274A CA1117541A CA 1117541 A CA1117541 A CA 1117541A CA 000363274 A CA000363274 A CA 000363274A CA 363274 A CA363274 A CA 363274A CA 1117541 A CA1117541 A CA 1117541A
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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
- C07D309/32—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
-
- 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
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pyridine Compounds (AREA)
- Cosmetics (AREA)
- Plural Heterocyclic Compounds (AREA)
- Furan Compounds (AREA)
- Saccharide Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Transforming Electric Information Into Light Information (AREA)
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- Processing Of Color Television Signals (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
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- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
ABSTRACT
The preparation 4-halo-dihydropyran intermediates by reacting (i) a substituted or unsubstituted 2H-pyran-3(6H)-one with at least one equivalent, or (ii) a furfuryl alcohol with at least two equivalents, of a halogen-contain-ing oxidant, selected from chlorine, bromine, bromine chloride, hypochlorous acid, hypobromous acid or a mixture thereof; and novel 4-halo-dihydro-pyran intermediates.
The preparation 4-halo-dihydropyran intermediates by reacting (i) a substituted or unsubstituted 2H-pyran-3(6H)-one with at least one equivalent, or (ii) a furfuryl alcohol with at least two equivalents, of a halogen-contain-ing oxidant, selected from chlorine, bromine, bromine chloride, hypochlorous acid, hypobromous acid or a mixture thereof; and novel 4-halo-dihydro-pyran intermediates.
Description
~ ~ .
This is a divisional of Patent Application No.
279922, filed June 6, 1977~
Applioation No. 279922 describe3 and claims the praparation of gamma-pyrones and partiaularly to the pre S para~ion of gama-pyrones by the hydrolysis of certain inter-mediate compounds, some of which are novel, which intermedi-ates are prepared from appropriate ~urfuryl alcohols by the u~e of halogen-contai~ing oxidant3. Appli~ation No. 27g922 al~o di3closes a one-pot process for preparing gamma-pyrone~
10 from furfuryl alc~hols. The pre~ent divisional is concern-ed with novel 4-halo-dihydropyran intermediates and the preparation thereof~
Maltol (2-methyl-3~hydroxy-4H-pyran-4-one) is a naturally occurring ~ubstance found in the bark of young 15 larch treesl pine needles and chiaory. Early commercial production was frcm the destructive di~tillation of wood.
The synthesi3 of maltol from 3-hydroxy-2-(1-piperidylmethyl)-1,4-pyrone was reported by Spielman and Freifelder in ~. Am.
Chem. Soc., 69 2908 ~1947). Schenck ana Spielman, J. Am.
20 Chem. Soc., 67, 2276 (1945), ob~ained maltol by alkaline hydrolysis of streptomycin salt3. Chawla and McGonigal, J. Org. Chem., 39, 3281 (1974) and ~ichtenthaler and Heidel, Angew. Chem., 81, 998 (1969), reported the synthe~is of mal~ol from protecked caxbohydrate derivatives. Shono and 25 Matsumura. Tetrahedron Letter~ No, 17, 1363 (1976), describ-ed a five step synthe~i~ o~ maltol starting with methyl furfuryl alcohol.
~The i olation of 6-methyl-2-ethyl-3-hydroxy-4H-., : .
~75~ ~
pyran-4-one as on~ of the charac~eristic sweet-aroma com-ponents in refinery final mola~ses waq reported by Hiro~hi I~o in Agr. siOl, Chem., 40 (5), 827-832 (1976). Thi~ com-pound was previou~ly ~ynthesized by the proce~s de~cribed 5 in United State~ Patent Speciflcation No~ 3,468,915.
Synthese~ o~ gamrna-pyrones such as pyrorneconic acid, maltol, ethyl maltol and o~her 2-~u~s~ituted-3-hydroxy-gamma-pyrones are de~cribed in United States Patent~ No.
3,130,20~; 3,133,0a9; 3,140,239; 3,159,~52; 3,365,469;
10 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 o food products. In addition, these compounds are u~ed as ingredientq in per~ume~ and essence~
The 2-alkenylpyromeconic acids reported in United States 15 Patent No. 3,644,63S and the 2-arylmethylpyromeconic acid de~cribed in United States Patsnt No. 3,365,469 inhibit the growth of baoteri and fungi and are useful a~ flavor and aroma enhancers in foods and beverages and aroma enhancers in perfumes.
Applica~ion No. 279922 provides a process for pre-paring a gamma-pyr~ne of the formula:
o ~ OH
,,) \ O ~ \R ...(I) which comprises heating i~l acidic aqueous solution, prefer-ably at a temperatur2 within the range of 70 to 160C., 25 until hydrolysi~ is ubstantially complete a 4-halo-dihydro-pyran of the ormula (II) or a 6,6'~oxybis~4-halo-2H-pyran-3(6H)-one] o~ the formula (V): .
X ~ X
B R~ O or ~\~
R'O O R R / ~ O ~ O O R
(II) (V) wherein R i~ hydrogen, alkyl of 1 to 4 carbon atoms, phenyl or ben~yl, R' i8 hydroyen, alkyl of 1 to 4 carbon atoms or -COR", wherein R" is methyl, ethyl or phenyl, R''' is hydro~
gen or alkyl of 1 ~o 4 carbon atom~, and X i~ chlorine or S bromine.
The acid required for the hydroly~is may be added to the reaction mixture, e.y. by di3~01ving the intermediate compound of formula (II) or formula (V~ in an aqueous inorganic or organic before heating; or alternatively the acid may be generated in situ during the preparation of the intermediates as hereinafter described.
In accordance with the present divi~ional thexe is provided a process for preparing the intermediate com-pound of formula (II) which comprises reacting a compound of the formula:
,~
R' ~ ¦ I
R'O `O ~ R ~ IV) wherein R, R' and R''' are a~ defined above, in a solvent at a temperature of -50 to 50C., preferably at room temperature, with at least one equivalent of a halogen-con-taining oxidan~ selected from chlorine, bromine, brominechloride, hypochlorou~ acid, hypobromous acid or mixtures thereof until the reaction is sub~tantially complet~r ~ xamples of suitable solvents for this reaction are water, an alkanol or diol of 1 to 4 carbon atoms, preferably methanol, an ether of 2 to 10 carbon atoms, preferably tetrahydrofuran or isopropyl ether, a low molecular weight ketone, preferably acetone, a low molecular weight nitrile, ester or amide.
The intermediate compound of formula (IV) above wherein R' is hydrogen may be prepared by reaoting a furfuryl alcohol o~ the formula:
R'.'~ ~ OH
" O ~ ~ R .~o(III) s~
wherein R and R'l' are as defined above, in aqueous solution wlth at least one equival~nt of a halogen-containing oxidant selected from chlorine, bromine, bromine chl~ride, hypochlorous acid, hypobromous acid or mixttlres thereof at a temperature of -50 to 50C , preferably room temperature, until the reaction is substantially complete~ me reaction may be conducted in the presence o a co-~olvent which suitably may be one of the ~olvents previously mentioned fox the preparation of the intarmediate compound of formula (II).
If desired, the in~ermediate 4-halo-dihydropyran compound of ormula (II) wherein R' i9 hydrogen may be pre-pared dixect from an appropriate furfuryl alcohol of fo~mula (III) by reacting the latter in an aqueous solvent at a temperature of -50 to 50 C., with at lea~t two equivalents of one of the aforementloned halogen-containing oxidants until the reaction is ~b3tantially complete.
In each of the above-de~cribed reactions the pre-ferred halogen-containing oxidant i9 chlorine or bromine chloride.
The intermediate compound of formula (V) may be prepared by dehydrating a compound of the formula:
X
L
H0 ~ 0 ~ \R ...~II") As disclosed in Application No. 279922 a novel and facile 6yn~hesis of gamma-pyrones of formula (I) above, particularly maltol (2-methyl-3-hydroxy-4H-pyran-4-one) and related compounds, may be provided by a one-pot process from a fur~uryl alaohol of formula (III) above.
In accordance with thi~ one-pot process, a furfuryl alcohol in a~ueous medium i~ reacted with two equivalents of a halogen-containlng oxidant and the reaction mixture is then heatad to hydrolyze the resulting inter-medlate, The one pot proces~ may be represented by the 1 ~l75~1 :~ollowing equation.
Ll OH
o~
... (III) ,,.(I) wherein R is hydrogen, alkyl of 1 to 4 carbon atoms, phenyl or ben~yl; R" ' is hydrogen or alkyl of 1 to 4 S carbon atoms; and XY i9 C12, Br2, ClBr, HOCl, HOBr or mix-tures thereof. The full reaction pathway i ~hown in the following scheme:
~ Oxidant O Y 1 R''' ~ o ~ ~ ~ ~
OH ~ ~ , (III) R" ~ `t~ ' R R"'~ f l R' " C-O
I open CH chain CH tautomer C~O
H- COH
R
X o R''' ~ O ~ R ''' ~ ~ R
OH ~II') (I) open chain tautomer Lefebvre and co-workers in J. M~d. Chem., 16, 1084 (1973) demonstrated that furfuryl alaohols could be directly converted to 6-hydroxy-2H-pyran-3~6H)ones when a peracid oxidant such a~ peracetic acid or m-chloroperbenzolc acid is employed~ The first stap of the Lefebvre work uses ~7~ ~
a peracid in an organic solvent and probably leads to a 6-acetoxy or 6 m-chlorobenzoyloxy pyran derivative ,1hich i3 hydrolyzed ~o ~he 6-hydroxy compound during ~he a~ueous work-up. water i~ not u3ed in the fir~t ~tep of the react-ion, and would in Eact be deleterious~ In any case, theproces~ of Lefebvre and co-worker~ cannot lead directly to the conver~ion of a furfuryl alcohol to A yamma-pyrone.
Critical to the process for the preparation of the intermediate~ of the pre~ent invention i9 the use of an aqueous solu~ion of a halogen-containing oxidant. A furfuryl alcohol may be cleanly oxidized to a 6-hydroxy-2H-pyran-3~6H)-one using one equivalent of a halogen-containing oxidant in water or water/organic co-solvent. It is a surprising and unexpected finding that 6-hydroxy-2H-pyran-3(6H)-ones can ~e converted to gamma-pyrone~ A 6-hydroxy-2H-pyran-3~6H)-one may be regarded as a hemi-aoetal of an aldehyde and as such might be expected to undergo num~rous undeslred side reactions such as over oxidation or an aldol-tvpe conden-sations. By employing two equivalents of a halogen-contain-ing oxidant in water or wa~er and organic co-solvent, khe raaction proceeds smoothly from a furfuryl alcohol to a gamma-pyrone This novel one pot process offer3 the advan-tages of employing low cost C12, Br2, BrCl, HOCl, HOBr or mixtures thereof as the halogen-containing oxidant. Isola tion of the desired gamma-pyrone is greatly simplified since solvent, oxidant and by-product mineral acid are all volatile and may be removed i_ vacuo to afford crude gamma~
pyrone directly in high yield by simple concentration~
The one pot process i~ operated by dis olving a furfuryl alcohol in water or water and a co-solvent. The co-~olvent may be water-miscible or water-immiscible and may be selected from a wide range of solvent~ such as Cl to C4 alkanols or diols, for example, mathanol; C2 to C10 ethers, for example, tetrahydro~uran or isopxopyl ether;
low molecular weight ketones, for example, acet~ne; low molecular weight ~itrile~; low molecular weight esters and low moleaular weight amides. The preferred co-solvents are Cl to C4 alkanols ~nd c2 to C10 ethers, ~.~ith methanol the choice ~f ~olvents becau~e of C09t. The ~olution ls kept at a temperature of -50 to 50C,, preferably -10 to 10C.
To ~his ~olution i8 charged a desired furfuryl alcohol whila simultaheously adding a halogen~containing oxidant (two equivalents) to th8 reaction mixture. The temperature of the reaction mixture is main~ained at -50 to 50C., preferably -10 to 1~C , during halogen addition. If a low-boiling co-solvent is employed, it is removed by dis-tillation after all additions are complete. The reactionmixture is then heated to a t~mperature at which the hydrolysis proceeds at a reasonable rate, for example, 70 to 160C. The generally employed hydrolysis temperature iq 100 to 110C. The heating is continued until the hydrolysis of the formed 4~halo-hydropyran intermediate is sub~tantially complete ~usual~y 1 to 2 hours)~ The acid necessary to catalyze this final hydrolysis is generated in situ by loss of acid from the intermediates formed during thP course o~ the reactionO Additional acid may be added if desired The halogen-containlng oxidant is selected from chlorine, bromine, bromine chloride, hypochlorous or hypobromous acid or mixtures thereof. Bromine chloride is a commercially available gas. It may be prepared in situ by the addition of chlorine to a solution of sodium or potassium bromine or by the addition of bromine to a solution of sodium or potassium chloride. Hypochlorous and hypobromou~ acid conveniently may be generated in itu by the addition of aqueous a~id (HCl, H2SO4 or HBr) to a solution of an alkali metal or alkaline earth metal hypo-halite, e.g., NaOCl, KOCl or Ca(OCl)2. The preferred halogen-containing oxidants, based on cost factors, are chlorine and bromine chloride prepared in situ.
As de~cribed above, khe intermediate 6-hydroxy-2H-pyran-3(6H)-one of formula (IV~ may be prepared by re-acting the appropriate furfuryl alcohol with one equivalent of a halogen-containing oxidant. The isolated intermediate 7~;;'1 ~
ls readily co~ve~ted to ~he desired gamma-pyrone by react-in~ it with an additional equivalent of a halogen oxidant and hydroly~ing the formed 4-halv-&-hydroxy-2H-pyran~3(6H)-one of formula (II) as previously de~aribed.
Alte~natively, a furfuryl alcohol in aqueou3 801u-tion with an optional co-~olvent may be reaated at -10 to 10C. with two equivalents o~ a halogen-containiny oxidant. After stirring at room temperAture for 30 minutes, the pH of ~he reac~ion mixtura i8 adju~ted to 2 with a strong base and the reaction mixture i3 extracted with a solvent ~uch as ethyl acetQte. ~emoval of the ~olvent yields the 4-halo-6-hydroxy-2H-pyran-3~6H)-one of foxmula (II') which may be hydrolyzed to the de~ired gamma-pyrone.
The 4-halo~dihydropyran may be dehydrated by heating under vacuum to yield the 6,6~-oxybis ~4-halo-2~-pyran-3(6H)-one].
This dimer yields the desired gamma-pyrone on hydroly~is, with added acid if desired.
Certain of th~ 4-halo-dihydropyran intermediate compounds are novel compounds and, accordingly, the present invention also provide~ a compound of the formula:
R' " ~ ~ ...(II') HO O R
wherein R, R' " and X are as defined above, and a compound of the formula:
R ' ~ ...(IV) R C2~5 wherein R and X are a deined above and R4 is alkyl of 1 to 4 carbon atoms or -COR" wherein ~" i8 m~thyl, ~thyl or phenyl, provided that when X is chlorin~ and R4 is ethyl, R' " i~ not hydrogen The 6,6'-oxybis [4-halo-2H-pyran-3(6H)~one]
intermediate compound o the formula:
31 ~3 7~
\X~ (V) R o / o o R
wherein R and X are a~ defined above, is also a ~ovel com-pound .
A 6-alkoxy-2H-pyxan-3(5H)-one may be prepared by the method dascribed in Tetrahedron Letters No. 17, 1363-1364 (1976). A furfuryl alcohol is anodically alkoxylatedto the 2~ hydroxyalkyl)~2,5-dialkoxy-dihydro-furan. Treatment with a strong oryanic acid produces the desired 6~alkoxy compound~ A 6-aayl compound may be pre-pared by ~onventional treatment of the 6-hydroxy compound with the appropriate anhydride in the presence of pvridine.
A 6-acyl or 6-alkoxy-2H-pyran-3(6H)-one i8 dis-solved in a solvent select~d from acetic acid, formic acid, trifluoroacetia aaid, halogenated solvents, ethexs, Cl to C4 alkanols or diols, or low molecular weight ketones, nitriles, esters or amide~. The preferred 601vent is acetic a~id, formic açid or methanol. An equivalent of a halogen-containing oxidant selected chlorine, bromine, bromine chloride, hypochlorous acid, hypobromous acid or mixtures thereof i8 added at room temperature and the reac~ion mixture is heated ~o 70-160C., genexally 100-110 C., until th~ conversion to the de~ired gamma-pyrone i9 substantially complete (approximately 1 to 3 hours)0 The gamm~-pyrone may be obtained from the cooled, neutralized reaction mixture on standing or by extracting the xeaction mixture with a solvent ~uch as chlorQform which yields the gamma-pyrone on concentration.
With organic acids and other protia solvents such a formic acid, acetic acid, other organic a~ids and alkanols that have not been vlgorously dried, no additional water is added in the above described reaction. However, with non-proti~ solvenks, water is nece~ary and is added for the conver~ion of the intermediate 4-halo-6-sub~tituted-2H-pyran-3(6H)-one to the pyrone. When a low-boiling ~ol-'~ ~J~7 ~ ~
vent is employed in the reaction it is removed by distill-ation just before the reaction mixture i~ heated to 100 to 110C. for the hydrolytic conversion of ~he intermediate 4-halo-dihydropyran to the gamma-py~o~e.
If desired, the 4-h~lo-dihydropyran may he pre-pared and isolated by conduating the halogenation at a temperature of -20 to 20C., pre~erably 5b~ 10C., in the presence of an oxganic base such a~ triethylamide.
After about 30 minutes khe reaction mixture is allowed to warm ~o room temperature, filtered to remove triethylamide hydrochloride and ~he solven~ removed under vacuum to yield the 4-halo-dihydropyran. This compound is readily hydrolyzed to the gamma-pyrone by haating for about an hour in aqueou~ solution, with added acid if desired, pre-ferably at a tempera~ure within the range of 70 to 160C., more preferably 100 t~ 110C.
Thi~ process wherein the 6-acyl or 6-alkoxy-2H-pyran-3(6~)-one is reacted in an organic ~olvent with one equivalent of a halogen-containing oxidant and the inter-mediate 4-halo-dihydropyran heated until the conversion to the de3ired gamma-pyrone is sub~tantiall~ complete difers from the multi-step process described by Shono and Matsumura in Tetrahedron Letters 17, 1363 ~1976) wherein the 6-alkoxy-2H-pyran-3(6H)-one i8 treated with a methanol-ic solution of hydrogen peroxide with sodium hydroxidesolution to yield an epoxy keton~. The i~olated epvxy ketone is then refluxed in water with "Dowex"* 50 ion exchange resin to yield the desired gamma-pyrone.
The following Examples illustrate the preparation of the gamma-pyrones according to tha proaess of the invention and the preparation o~ the various intermediate compound~, In the Examples where spe~tral data are give, NMR chemical shift data are reported by aonventional literature symboli~m and all shifts are expre~sed as units rom tetramethyl silane:
~a~--~; a singlet d = doublat t = triplet ~ = quartet m = multipl~t br ~ broad Example 1 In a 3-neck round bo~ton ~lask equipp~d with a magnetic stirring barl a gas inlet tube, a thermometex and an additional funnel was added 20 ml of tetrahydrofuran and 50 ml of water. The 801ution was cooled to a tempera-ture of 0 ~o 10C. The addition funnel was charged with a solution of 1(2-furyl)-1-athanol (00~89 mole~) in 20 ml of tetrahydrofuran and ~his was added dropwise to th~
stirred reaction flask while chlorine (0.30 mole) was added via th~ gas inlet tube~ The rate of addition was such that all the alcohol was added in the fir3t 1.3 to 1.5 equivalents of chlorine ~approximately 30 minutes) while maintaining the temperature below 10C. The reaction mixture was heated to reflux and the tetrahydrofuran re-moved by distillation. When the re~ction mixture reached a temperature o~ about 105C., a condensor was added and the refluxing continued for about 2 hours. The reaction mixture was then filtered hot, cooled, the pH adjusted to 2~2 and the reaction mixture wa~ cooled to 5C. Crystallization and filtration yielded 3.43 grams of crude 3-hydroxy-2-methyl-~-pyrone ~maltol). The aqueous filtrate was ex-tracted with chloroform to ~btain a second crop of 2.58 g of maltol. Distillation of the combined solids and re-crystallization from methanol gave 5.5 g ~49%) of purewhite maltol, m.p. 159.5 to 160.5C.
~ 2 The procedure of Example 1 was repeated under varying conditions as shown in Tablc I with furfu~yl alcohol~ of the formula 7~
-12~
\O <
R
Table 1. One Pot Process u~.ing chlorine a~ the oxidant.
-Temp. Temp.
(C) of ~C) o ~ield ~ osolvent oxldatlon_ hydrolysis ~
CH3 methanol 10 100 45 CH3 methanol 5 110 56 CH3 methanol -5 104 60 CH3 methanol ~10 104 77 CH3 methanol -20 106 62-67 CH3 acetone -5 110 36 CH3 EtOAc 0 110 26 CH3 none 10 110 17-30 CH3 benzene 10 110 26 CH3 methyl isobutyl ketone S 110 44 CH isopropyl 3 alcohol 0 110 49 CH3 methanol 5 110 49 CH3 methanol -10 110 58 H methanol -10 110 57 CH3 methanol -30 110 50 THF = tetrahydrofuran EtOAc - ethyl acetate ~.
The method of Example 2 wa~ repeated with ~om-parable results employing each of the following co-solvents:
ethanol n-propanol iso-bu~anol n-butanol t-butanol dioxane ethyl ether i~opropyl ether dimethoxy ethane
This is a divisional of Patent Application No.
279922, filed June 6, 1977~
Applioation No. 279922 describe3 and claims the praparation of gamma-pyrones and partiaularly to the pre S para~ion of gama-pyrones by the hydrolysis of certain inter-mediate compounds, some of which are novel, which intermedi-ates are prepared from appropriate ~urfuryl alcohols by the u~e of halogen-contai~ing oxidant3. Appli~ation No. 27g922 al~o di3closes a one-pot process for preparing gamma-pyrone~
10 from furfuryl alc~hols. The pre~ent divisional is concern-ed with novel 4-halo-dihydropyran intermediates and the preparation thereof~
Maltol (2-methyl-3~hydroxy-4H-pyran-4-one) is a naturally occurring ~ubstance found in the bark of young 15 larch treesl pine needles and chiaory. Early commercial production was frcm the destructive di~tillation of wood.
The synthesi3 of maltol from 3-hydroxy-2-(1-piperidylmethyl)-1,4-pyrone was reported by Spielman and Freifelder in ~. Am.
Chem. Soc., 69 2908 ~1947). Schenck ana Spielman, J. Am.
20 Chem. Soc., 67, 2276 (1945), ob~ained maltol by alkaline hydrolysis of streptomycin salt3. Chawla and McGonigal, J. Org. Chem., 39, 3281 (1974) and ~ichtenthaler and Heidel, Angew. Chem., 81, 998 (1969), reported the synthe~is of mal~ol from protecked caxbohydrate derivatives. Shono and 25 Matsumura. Tetrahedron Letter~ No, 17, 1363 (1976), describ-ed a five step synthe~i~ o~ maltol starting with methyl furfuryl alcohol.
~The i olation of 6-methyl-2-ethyl-3-hydroxy-4H-., : .
~75~ ~
pyran-4-one as on~ of the charac~eristic sweet-aroma com-ponents in refinery final mola~ses waq reported by Hiro~hi I~o in Agr. siOl, Chem., 40 (5), 827-832 (1976). Thi~ com-pound was previou~ly ~ynthesized by the proce~s de~cribed 5 in United State~ Patent Speciflcation No~ 3,468,915.
Synthese~ o~ gamrna-pyrones such as pyrorneconic acid, maltol, ethyl maltol and o~her 2-~u~s~ituted-3-hydroxy-gamma-pyrones are de~cribed in United States Patent~ No.
3,130,20~; 3,133,0a9; 3,140,239; 3,159,~52; 3,365,469;
10 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 o food products. In addition, these compounds are u~ed as ingredientq in per~ume~ and essence~
The 2-alkenylpyromeconic acids reported in United States 15 Patent No. 3,644,63S and the 2-arylmethylpyromeconic acid de~cribed in United States Patsnt No. 3,365,469 inhibit the growth of baoteri and fungi and are useful a~ flavor and aroma enhancers in foods and beverages and aroma enhancers in perfumes.
Applica~ion No. 279922 provides a process for pre-paring a gamma-pyr~ne of the formula:
o ~ OH
,,) \ O ~ \R ...(I) which comprises heating i~l acidic aqueous solution, prefer-ably at a temperatur2 within the range of 70 to 160C., 25 until hydrolysi~ is ubstantially complete a 4-halo-dihydro-pyran of the ormula (II) or a 6,6'~oxybis~4-halo-2H-pyran-3(6H)-one] o~ the formula (V): .
X ~ X
B R~ O or ~\~
R'O O R R / ~ O ~ O O R
(II) (V) wherein R i~ hydrogen, alkyl of 1 to 4 carbon atoms, phenyl or ben~yl, R' i8 hydroyen, alkyl of 1 to 4 carbon atoms or -COR", wherein R" is methyl, ethyl or phenyl, R''' is hydro~
gen or alkyl of 1 ~o 4 carbon atom~, and X i~ chlorine or S bromine.
The acid required for the hydroly~is may be added to the reaction mixture, e.y. by di3~01ving the intermediate compound of formula (II) or formula (V~ in an aqueous inorganic or organic before heating; or alternatively the acid may be generated in situ during the preparation of the intermediates as hereinafter described.
In accordance with the present divi~ional thexe is provided a process for preparing the intermediate com-pound of formula (II) which comprises reacting a compound of the formula:
,~
R' ~ ¦ I
R'O `O ~ R ~ IV) wherein R, R' and R''' are a~ defined above, in a solvent at a temperature of -50 to 50C., preferably at room temperature, with at least one equivalent of a halogen-con-taining oxidan~ selected from chlorine, bromine, brominechloride, hypochlorou~ acid, hypobromous acid or mixtures thereof until the reaction is sub~tantially complet~r ~ xamples of suitable solvents for this reaction are water, an alkanol or diol of 1 to 4 carbon atoms, preferably methanol, an ether of 2 to 10 carbon atoms, preferably tetrahydrofuran or isopropyl ether, a low molecular weight ketone, preferably acetone, a low molecular weight nitrile, ester or amide.
The intermediate compound of formula (IV) above wherein R' is hydrogen may be prepared by reaoting a furfuryl alcohol o~ the formula:
R'.'~ ~ OH
" O ~ ~ R .~o(III) s~
wherein R and R'l' are as defined above, in aqueous solution wlth at least one equival~nt of a halogen-containing oxidant selected from chlorine, bromine, bromine chl~ride, hypochlorous acid, hypobromous acid or mixttlres thereof at a temperature of -50 to 50C , preferably room temperature, until the reaction is substantially complete~ me reaction may be conducted in the presence o a co-~olvent which suitably may be one of the ~olvents previously mentioned fox the preparation of the intarmediate compound of formula (II).
If desired, the in~ermediate 4-halo-dihydropyran compound of ormula (II) wherein R' i9 hydrogen may be pre-pared dixect from an appropriate furfuryl alcohol of fo~mula (III) by reacting the latter in an aqueous solvent at a temperature of -50 to 50 C., with at lea~t two equivalents of one of the aforementloned halogen-containing oxidants until the reaction is ~b3tantially complete.
In each of the above-de~cribed reactions the pre-ferred halogen-containing oxidant i9 chlorine or bromine chloride.
The intermediate compound of formula (V) may be prepared by dehydrating a compound of the formula:
X
L
H0 ~ 0 ~ \R ...~II") As disclosed in Application No. 279922 a novel and facile 6yn~hesis of gamma-pyrones of formula (I) above, particularly maltol (2-methyl-3-hydroxy-4H-pyran-4-one) and related compounds, may be provided by a one-pot process from a fur~uryl alaohol of formula (III) above.
In accordance with thi~ one-pot process, a furfuryl alcohol in a~ueous medium i~ reacted with two equivalents of a halogen-containlng oxidant and the reaction mixture is then heatad to hydrolyze the resulting inter-medlate, The one pot proces~ may be represented by the 1 ~l75~1 :~ollowing equation.
Ll OH
o~
... (III) ,,.(I) wherein R is hydrogen, alkyl of 1 to 4 carbon atoms, phenyl or ben~yl; R" ' is hydrogen or alkyl of 1 to 4 S carbon atoms; and XY i9 C12, Br2, ClBr, HOCl, HOBr or mix-tures thereof. The full reaction pathway i ~hown in the following scheme:
~ Oxidant O Y 1 R''' ~ o ~ ~ ~ ~
OH ~ ~ , (III) R" ~ `t~ ' R R"'~ f l R' " C-O
I open CH chain CH tautomer C~O
H- COH
R
X o R''' ~ O ~ R ''' ~ ~ R
OH ~II') (I) open chain tautomer Lefebvre and co-workers in J. M~d. Chem., 16, 1084 (1973) demonstrated that furfuryl alaohols could be directly converted to 6-hydroxy-2H-pyran-3~6H)ones when a peracid oxidant such a~ peracetic acid or m-chloroperbenzolc acid is employed~ The first stap of the Lefebvre work uses ~7~ ~
a peracid in an organic solvent and probably leads to a 6-acetoxy or 6 m-chlorobenzoyloxy pyran derivative ,1hich i3 hydrolyzed ~o ~he 6-hydroxy compound during ~he a~ueous work-up. water i~ not u3ed in the fir~t ~tep of the react-ion, and would in Eact be deleterious~ In any case, theproces~ of Lefebvre and co-worker~ cannot lead directly to the conver~ion of a furfuryl alcohol to A yamma-pyrone.
Critical to the process for the preparation of the intermediate~ of the pre~ent invention i9 the use of an aqueous solu~ion of a halogen-containing oxidant. A furfuryl alcohol may be cleanly oxidized to a 6-hydroxy-2H-pyran-3~6H)-one using one equivalent of a halogen-containing oxidant in water or water/organic co-solvent. It is a surprising and unexpected finding that 6-hydroxy-2H-pyran-3(6H)-ones can ~e converted to gamma-pyrone~ A 6-hydroxy-2H-pyran-3~6H)-one may be regarded as a hemi-aoetal of an aldehyde and as such might be expected to undergo num~rous undeslred side reactions such as over oxidation or an aldol-tvpe conden-sations. By employing two equivalents of a halogen-contain-ing oxidant in water or wa~er and organic co-solvent, khe raaction proceeds smoothly from a furfuryl alcohol to a gamma-pyrone This novel one pot process offer3 the advan-tages of employing low cost C12, Br2, BrCl, HOCl, HOBr or mixtures thereof as the halogen-containing oxidant. Isola tion of the desired gamma-pyrone is greatly simplified since solvent, oxidant and by-product mineral acid are all volatile and may be removed i_ vacuo to afford crude gamma~
pyrone directly in high yield by simple concentration~
The one pot process i~ operated by dis olving a furfuryl alcohol in water or water and a co-solvent. The co-~olvent may be water-miscible or water-immiscible and may be selected from a wide range of solvent~ such as Cl to C4 alkanols or diols, for example, mathanol; C2 to C10 ethers, for example, tetrahydro~uran or isopxopyl ether;
low molecular weight ketones, for example, acet~ne; low molecular weight ~itrile~; low molecular weight esters and low moleaular weight amides. The preferred co-solvents are Cl to C4 alkanols ~nd c2 to C10 ethers, ~.~ith methanol the choice ~f ~olvents becau~e of C09t. The ~olution ls kept at a temperature of -50 to 50C,, preferably -10 to 10C.
To ~his ~olution i8 charged a desired furfuryl alcohol whila simultaheously adding a halogen~containing oxidant (two equivalents) to th8 reaction mixture. The temperature of the reaction mixture is main~ained at -50 to 50C., preferably -10 to 1~C , during halogen addition. If a low-boiling co-solvent is employed, it is removed by dis-tillation after all additions are complete. The reactionmixture is then heated to a t~mperature at which the hydrolysis proceeds at a reasonable rate, for example, 70 to 160C. The generally employed hydrolysis temperature iq 100 to 110C. The heating is continued until the hydrolysis of the formed 4~halo-hydropyran intermediate is sub~tantially complete ~usual~y 1 to 2 hours)~ The acid necessary to catalyze this final hydrolysis is generated in situ by loss of acid from the intermediates formed during thP course o~ the reactionO Additional acid may be added if desired The halogen-containlng oxidant is selected from chlorine, bromine, bromine chloride, hypochlorous or hypobromous acid or mixtures thereof. Bromine chloride is a commercially available gas. It may be prepared in situ by the addition of chlorine to a solution of sodium or potassium bromine or by the addition of bromine to a solution of sodium or potassium chloride. Hypochlorous and hypobromou~ acid conveniently may be generated in itu by the addition of aqueous a~id (HCl, H2SO4 or HBr) to a solution of an alkali metal or alkaline earth metal hypo-halite, e.g., NaOCl, KOCl or Ca(OCl)2. The preferred halogen-containing oxidants, based on cost factors, are chlorine and bromine chloride prepared in situ.
As de~cribed above, khe intermediate 6-hydroxy-2H-pyran-3(6H)-one of formula (IV~ may be prepared by re-acting the appropriate furfuryl alcohol with one equivalent of a halogen-containing oxidant. The isolated intermediate 7~;;'1 ~
ls readily co~ve~ted to ~he desired gamma-pyrone by react-in~ it with an additional equivalent of a halogen oxidant and hydroly~ing the formed 4-halv-&-hydroxy-2H-pyran~3(6H)-one of formula (II) as previously de~aribed.
Alte~natively, a furfuryl alcohol in aqueou3 801u-tion with an optional co-~olvent may be reaated at -10 to 10C. with two equivalents o~ a halogen-containiny oxidant. After stirring at room temperAture for 30 minutes, the pH of ~he reac~ion mixtura i8 adju~ted to 2 with a strong base and the reaction mixture i3 extracted with a solvent ~uch as ethyl acetQte. ~emoval of the ~olvent yields the 4-halo-6-hydroxy-2H-pyran-3~6H)-one of foxmula (II') which may be hydrolyzed to the de~ired gamma-pyrone.
The 4-halo~dihydropyran may be dehydrated by heating under vacuum to yield the 6,6~-oxybis ~4-halo-2~-pyran-3(6H)-one].
This dimer yields the desired gamma-pyrone on hydroly~is, with added acid if desired.
Certain of th~ 4-halo-dihydropyran intermediate compounds are novel compounds and, accordingly, the present invention also provide~ a compound of the formula:
R' " ~ ~ ...(II') HO O R
wherein R, R' " and X are as defined above, and a compound of the formula:
R ' ~ ...(IV) R C2~5 wherein R and X are a deined above and R4 is alkyl of 1 to 4 carbon atoms or -COR" wherein ~" i8 m~thyl, ~thyl or phenyl, provided that when X is chlorin~ and R4 is ethyl, R' " i~ not hydrogen The 6,6'-oxybis [4-halo-2H-pyran-3(6H)~one]
intermediate compound o the formula:
31 ~3 7~
\X~ (V) R o / o o R
wherein R and X are a~ defined above, is also a ~ovel com-pound .
A 6-alkoxy-2H-pyxan-3(5H)-one may be prepared by the method dascribed in Tetrahedron Letters No. 17, 1363-1364 (1976). A furfuryl alcohol is anodically alkoxylatedto the 2~ hydroxyalkyl)~2,5-dialkoxy-dihydro-furan. Treatment with a strong oryanic acid produces the desired 6~alkoxy compound~ A 6-aayl compound may be pre-pared by ~onventional treatment of the 6-hydroxy compound with the appropriate anhydride in the presence of pvridine.
A 6-acyl or 6-alkoxy-2H-pyran-3(6H)-one i8 dis-solved in a solvent select~d from acetic acid, formic acid, trifluoroacetia aaid, halogenated solvents, ethexs, Cl to C4 alkanols or diols, or low molecular weight ketones, nitriles, esters or amide~. The preferred 601vent is acetic a~id, formic açid or methanol. An equivalent of a halogen-containing oxidant selected chlorine, bromine, bromine chloride, hypochlorous acid, hypobromous acid or mixtures thereof i8 added at room temperature and the reac~ion mixture is heated ~o 70-160C., genexally 100-110 C., until th~ conversion to the de~ired gamma-pyrone i9 substantially complete (approximately 1 to 3 hours)0 The gamm~-pyrone may be obtained from the cooled, neutralized reaction mixture on standing or by extracting the xeaction mixture with a solvent ~uch as chlorQform which yields the gamma-pyrone on concentration.
With organic acids and other protia solvents such a formic acid, acetic acid, other organic a~ids and alkanols that have not been vlgorously dried, no additional water is added in the above described reaction. However, with non-proti~ solvenks, water is nece~ary and is added for the conver~ion of the intermediate 4-halo-6-sub~tituted-2H-pyran-3(6H)-one to the pyrone. When a low-boiling ~ol-'~ ~J~7 ~ ~
vent is employed in the reaction it is removed by distill-ation just before the reaction mixture i~ heated to 100 to 110C. for the hydrolytic conversion of ~he intermediate 4-halo-dihydropyran to the gamma-py~o~e.
If desired, the 4-h~lo-dihydropyran may he pre-pared and isolated by conduating the halogenation at a temperature of -20 to 20C., pre~erably 5b~ 10C., in the presence of an oxganic base such a~ triethylamide.
After about 30 minutes khe reaction mixture is allowed to warm ~o room temperature, filtered to remove triethylamide hydrochloride and ~he solven~ removed under vacuum to yield the 4-halo-dihydropyran. This compound is readily hydrolyzed to the gamma-pyrone by haating for about an hour in aqueou~ solution, with added acid if desired, pre-ferably at a tempera~ure within the range of 70 to 160C., more preferably 100 t~ 110C.
Thi~ process wherein the 6-acyl or 6-alkoxy-2H-pyran-3(6~)-one is reacted in an organic ~olvent with one equivalent of a halogen-containing oxidant and the inter-mediate 4-halo-dihydropyran heated until the conversion to the de3ired gamma-pyrone is sub~tantiall~ complete difers from the multi-step process described by Shono and Matsumura in Tetrahedron Letters 17, 1363 ~1976) wherein the 6-alkoxy-2H-pyran-3(6H)-one i8 treated with a methanol-ic solution of hydrogen peroxide with sodium hydroxidesolution to yield an epoxy keton~. The i~olated epvxy ketone is then refluxed in water with "Dowex"* 50 ion exchange resin to yield the desired gamma-pyrone.
The following Examples illustrate the preparation of the gamma-pyrones according to tha proaess of the invention and the preparation o~ the various intermediate compound~, In the Examples where spe~tral data are give, NMR chemical shift data are reported by aonventional literature symboli~m and all shifts are expre~sed as units rom tetramethyl silane:
~a~--~; a singlet d = doublat t = triplet ~ = quartet m = multipl~t br ~ broad Example 1 In a 3-neck round bo~ton ~lask equipp~d with a magnetic stirring barl a gas inlet tube, a thermometex and an additional funnel was added 20 ml of tetrahydrofuran and 50 ml of water. The 801ution was cooled to a tempera-ture of 0 ~o 10C. The addition funnel was charged with a solution of 1(2-furyl)-1-athanol (00~89 mole~) in 20 ml of tetrahydrofuran and ~his was added dropwise to th~
stirred reaction flask while chlorine (0.30 mole) was added via th~ gas inlet tube~ The rate of addition was such that all the alcohol was added in the fir3t 1.3 to 1.5 equivalents of chlorine ~approximately 30 minutes) while maintaining the temperature below 10C. The reaction mixture was heated to reflux and the tetrahydrofuran re-moved by distillation. When the re~ction mixture reached a temperature o~ about 105C., a condensor was added and the refluxing continued for about 2 hours. The reaction mixture was then filtered hot, cooled, the pH adjusted to 2~2 and the reaction mixture wa~ cooled to 5C. Crystallization and filtration yielded 3.43 grams of crude 3-hydroxy-2-methyl-~-pyrone ~maltol). The aqueous filtrate was ex-tracted with chloroform to ~btain a second crop of 2.58 g of maltol. Distillation of the combined solids and re-crystallization from methanol gave 5.5 g ~49%) of purewhite maltol, m.p. 159.5 to 160.5C.
~ 2 The procedure of Example 1 was repeated under varying conditions as shown in Tablc I with furfu~yl alcohol~ of the formula 7~
-12~
\O <
R
Table 1. One Pot Process u~.ing chlorine a~ the oxidant.
-Temp. Temp.
(C) of ~C) o ~ield ~ osolvent oxldatlon_ hydrolysis ~
CH3 methanol 10 100 45 CH3 methanol 5 110 56 CH3 methanol -5 104 60 CH3 methanol ~10 104 77 CH3 methanol -20 106 62-67 CH3 acetone -5 110 36 CH3 EtOAc 0 110 26 CH3 none 10 110 17-30 CH3 benzene 10 110 26 CH3 methyl isobutyl ketone S 110 44 CH isopropyl 3 alcohol 0 110 49 CH3 methanol 5 110 49 CH3 methanol -10 110 58 H methanol -10 110 57 CH3 methanol -30 110 50 THF = tetrahydrofuran EtOAc - ethyl acetate ~.
The method of Example 2 wa~ repeated with ~om-parable results employing each of the following co-solvents:
ethanol n-propanol iso-bu~anol n-butanol t-butanol dioxane ethyl ether i~opropyl ether dimethoxy ethane
2-methoxy ethanol 2-ethoxy ethanol ethylene ylycol ~,.
In a 3-neck round bottom flask equipped with a stirring bar, a gas inlet tube and an addition funnel was added 20 ml of tetrahydrofuran, 50 ml ~f water and sodium bromide (0.20 mole). The solution was cooled to a tempera-ture of 0~ to 20C. The addi~ion funnel wa~ charged with a solution o~ 1~2-furyl)-1-ethanol (0~18 mole) in 20 ml of tetrahydro~uran and thi8 was added dropwi~e ko the rapidly stirred reaction flask while gaseous chlorine ~0~40 mole) was added via the gaseous inlet tube. The xate of the alcohol addition was such that a yellow orange color was maintained, The tempexature wa~ kept below 20C. with ice bath oooling. After the alaohol and chlorine had both been added to the rea~kion ~lask, the temperature was ra~ed to reflux to distill off the tetrahydrofuran.
me i901ation procedure of Example 1 was used to isolate 12.47 g of pure maltol (55% yield).
Substantially the same re~ults were obtained substituting potassium bromide for sodium bromide.
Example 5 The method of Example 4 was repeated under varying conditions shown in Table 2 with furfuryl alcohols of the formula OH
o~
7~
Table 2. One Pot Process u~ng ~Cl a~ the oxidant, genera~-ed by addltion of chlorlne in ~itu t~ NaBr~
Tamp~ Temp, (C) of ~C) ofYield R Coiolvent oxidationhvdrolvsi~ (%) CH3 THF 20 o 104 55 CEl3 THF 15 110 52 CH3 Isopropyl ether 25 llO 46 lO CH3 ethyl eth~r 20 110 43 CH3 acetone 15 105 47 15 CH3 ~HF 16 113 47 .
THF = ~etrahydrofuran Exam~e 6 In a 3-neck round bottom fla~k e~uipped with a magnetic s~irring bar, a gas inlet tuhe, a thermometer and , an addition funnel was added 50 ml of tetrahydrofuran and 50 ml of water. This solution was then cooled to 0C. and chlorine ~0.10 mole) was added slowly to the reaction flask 25 while 1(2-furyl)~l-ethanol (0~09 mole) was added dropwise.
The temperature of the rea~tion mixture was not allowed to exceed 10C. Bromine (0.10 mole) was then added and the reaction mixture heated to reflux. Following the isolation procedure of Example 1, a yield of 5.7 g of mal~ol was 30 obtained.
~.
To a 4-neck round bottom flask e~uipped with a thermometer, a aonden30r and two addition funnel3 was charged 50 ml of tetrahydrofuran and 50 ml o~ water and the 35 solution was cooled to 10C. To this well stirred solution was added together in the ~wo addi~ion funnels bromine (0.20 mole) and 1~2-furYl~ ethanol (Q.Og mola). The ~7~1 temperature of the mixtur~ was maintained at 15C. throuyh-out the double addition. The xeaction mixture was then heated to 75C. for 10 hour.~, Maltol was i~olated by the procedure o ~xample 1 (53~ yield), ~
The me~hod of Example 7 was repeated under vary-ing conditions shown in Table 3 with fururyl alcohols of the formula 10Table 3 Temp, Temp.
(C) of ~,C) of Yield R _ Cosolv~nt _ oxidation _ hydrolysis ~%) _ CH3 THF lS~ 75 53 lS CH3 CH30H 5 lOS 47 CH3 none 15 100 30 Exam~le 9 A 2.8 M sodium hypochlorite solution was prepared by passing chl~rine ga3 ~42.6 g) into a solution of 48 g of sodium hydroxide in lS0 ml of water at 0C. A solution 25 of 1~2 furyl)-l-ethanol ~O.OS mole) in lS ml of tetrahydro-furan and 15 ml of water was prepared in a 3-neck flask and cooled to 5C. While maintaining a pH from 1.O to 0.8 with 6 N HCl, 21.7 ml o~ ~he hypochlorite solution was added dropwi~e to the reaction fla~k over a period of about 33 30 minutes while maintaining the temperature below 5C. A
15 ml portion of concentr~ted hydrochloric acid was then added to the reaction mixture which was then heated to rqmove the tetrahydrofuran by distillation. Heating was continued for an additional hour. Maltol was isolated as described 35 in Example 1.
~7~
Sub~tan~ially the same xesults are obtained when sodium hypobromite is used in place of sodium hypochlorite.
To a solution of 1~2~furyl)-1-ethanol ~0.05 mole~
5 in 15 ml of tetrahydrofuran and 15 ml of water at 5C. wa~
added 21.7 ml of 2.8 M sodium hypochlorite ~olution.
Chlorine ~0.05 mole) was added to the reaction flask via a gas inlet tube while maintaining the temperature below 5c, The reaction mixture was then heated to reflux and the tetra-10 hydrofuran removed by distillation. Heating wa~ continuedfor an additional hour. The reaction mixture was cooled and maltol wa~ i~olated by the pro~edure desaribed in Example 1.
To a 3-neck round bottom flask was charged a solu~
tion of 50 ml o~ water and 20 ml of tetrahydrofuran and the solution was cooled to 0C. An addition funnel wa~ charged with a solution of 1~2-furyl)-l~ethanol ~0.89 mole) in 25 ml of tetrahydrofuran and this ~olution was added dropwise ts 20 the reaction ~la~k while BrCl ~0~30 mole~ was added via a gas inlet tube. The rate of addi~ion was ~uch that all the furfuryl alcohol wa~ added in the first 1.3 to 1.5 equival-ents of BrCl while maintaining the temperature below 30C.
The reaction mixture was heated to reflux and the tetrahydro-25 furan removed by distilla~ion. When the temperature reached105C., ~ condensor was attached and the reaction mixture heated under r~flux for about 2 hour~. The reaction mixture was cooled and maltol isolated hy the procedure of ~ .
In a 3-nec~s round bottom flask equipped with a magnetic bar, a thermometer and two addition funnels was charged 25 ml o~ tetrahydrofuran and 50 ml of water. To this solution wa3 added 1(2-furyl)-1-ethanol ~0.89 mole) in 25 ml of tetrahydrouran while bromine ~0.16 mole) was added 35 dropwise while maintaining the tamper~ture below 15C. After the addition~ were complete, chlorine, chlorine ~0.10 mola) was added via a gas inlet tube and the reaction was heated ~75;~ ~
to reflux. Maltol was i~olated ~rom the cooled solution by the procedure of Example 1.
In a 3-neck round bottom flask equipped with a stirring bar, a gas inlet tube and an addition funnel was added 20 ml of tetrahydrofuran, 50 ml ~f water and sodium bromide (0.20 mole). The solution was cooled to a tempera-ture of 0~ to 20C. The addi~ion funnel wa~ charged with a solution o~ 1~2-furyl)-1-ethanol (0~18 mole) in 20 ml of tetrahydro~uran and thi8 was added dropwi~e ko the rapidly stirred reaction flask while gaseous chlorine ~0~40 mole) was added via the gaseous inlet tube. The xate of the alcohol addition was such that a yellow orange color was maintained, The tempexature wa~ kept below 20C. with ice bath oooling. After the alaohol and chlorine had both been added to the rea~kion ~lask, the temperature was ra~ed to reflux to distill off the tetrahydrofuran.
me i901ation procedure of Example 1 was used to isolate 12.47 g of pure maltol (55% yield).
Substantially the same re~ults were obtained substituting potassium bromide for sodium bromide.
Example 5 The method of Example 4 was repeated under varying conditions shown in Table 2 with furfuryl alcohols of the formula OH
o~
7~
Table 2. One Pot Process u~ng ~Cl a~ the oxidant, genera~-ed by addltion of chlorlne in ~itu t~ NaBr~
Tamp~ Temp, (C) of ~C) ofYield R Coiolvent oxidationhvdrolvsi~ (%) CH3 THF 20 o 104 55 CEl3 THF 15 110 52 CH3 Isopropyl ether 25 llO 46 lO CH3 ethyl eth~r 20 110 43 CH3 acetone 15 105 47 15 CH3 ~HF 16 113 47 .
THF = ~etrahydrofuran Exam~e 6 In a 3-neck round bottom fla~k e~uipped with a magnetic s~irring bar, a gas inlet tuhe, a thermometer and , an addition funnel was added 50 ml of tetrahydrofuran and 50 ml of water. This solution was then cooled to 0C. and chlorine ~0.10 mole) was added slowly to the reaction flask 25 while 1(2-furyl)~l-ethanol (0~09 mole) was added dropwise.
The temperature of the rea~tion mixture was not allowed to exceed 10C. Bromine (0.10 mole) was then added and the reaction mixture heated to reflux. Following the isolation procedure of Example 1, a yield of 5.7 g of mal~ol was 30 obtained.
~.
To a 4-neck round bottom flask e~uipped with a thermometer, a aonden30r and two addition funnel3 was charged 50 ml of tetrahydrofuran and 50 ml o~ water and the 35 solution was cooled to 10C. To this well stirred solution was added together in the ~wo addi~ion funnels bromine (0.20 mole) and 1~2-furYl~ ethanol (Q.Og mola). The ~7~1 temperature of the mixtur~ was maintained at 15C. throuyh-out the double addition. The xeaction mixture was then heated to 75C. for 10 hour.~, Maltol was i~olated by the procedure o ~xample 1 (53~ yield), ~
The me~hod of Example 7 was repeated under vary-ing conditions shown in Table 3 with fururyl alcohols of the formula 10Table 3 Temp, Temp.
(C) of ~,C) of Yield R _ Cosolv~nt _ oxidation _ hydrolysis ~%) _ CH3 THF lS~ 75 53 lS CH3 CH30H 5 lOS 47 CH3 none 15 100 30 Exam~le 9 A 2.8 M sodium hypochlorite solution was prepared by passing chl~rine ga3 ~42.6 g) into a solution of 48 g of sodium hydroxide in lS0 ml of water at 0C. A solution 25 of 1~2 furyl)-l-ethanol ~O.OS mole) in lS ml of tetrahydro-furan and 15 ml of water was prepared in a 3-neck flask and cooled to 5C. While maintaining a pH from 1.O to 0.8 with 6 N HCl, 21.7 ml o~ ~he hypochlorite solution was added dropwi~e to the reaction fla~k over a period of about 33 30 minutes while maintaining the temperature below 5C. A
15 ml portion of concentr~ted hydrochloric acid was then added to the reaction mixture which was then heated to rqmove the tetrahydrofuran by distillation. Heating was continued for an additional hour. Maltol was isolated as described 35 in Example 1.
~7~
Sub~tan~ially the same xesults are obtained when sodium hypobromite is used in place of sodium hypochlorite.
To a solution of 1~2~furyl)-1-ethanol ~0.05 mole~
5 in 15 ml of tetrahydrofuran and 15 ml of water at 5C. wa~
added 21.7 ml of 2.8 M sodium hypochlorite ~olution.
Chlorine ~0.05 mole) was added to the reaction flask via a gas inlet tube while maintaining the temperature below 5c, The reaction mixture was then heated to reflux and the tetra-10 hydrofuran removed by distillation. Heating wa~ continuedfor an additional hour. The reaction mixture was cooled and maltol wa~ i~olated by the pro~edure desaribed in Example 1.
To a 3-neck round bottom flask was charged a solu~
tion of 50 ml o~ water and 20 ml of tetrahydrofuran and the solution was cooled to 0C. An addition funnel wa~ charged with a solution of 1~2-furyl)-l~ethanol ~0.89 mole) in 25 ml of tetrahydrofuran and this ~olution was added dropwise ts 20 the reaction ~la~k while BrCl ~0~30 mole~ was added via a gas inlet tube. The rate of addi~ion was ~uch that all the furfuryl alcohol wa~ added in the first 1.3 to 1.5 equival-ents of BrCl while maintaining the temperature below 30C.
The reaction mixture was heated to reflux and the tetrahydro-25 furan removed by distilla~ion. When the temperature reached105C., ~ condensor was attached and the reaction mixture heated under r~flux for about 2 hour~. The reaction mixture was cooled and maltol isolated hy the procedure of ~ .
In a 3-nec~s round bottom flask equipped with a magnetic bar, a thermometer and two addition funnels was charged 25 ml o~ tetrahydrofuran and 50 ml of water. To this solution wa3 added 1(2-furyl)-1-ethanol ~0.89 mole) in 25 ml of tetrahydrouran while bromine ~0.16 mole) was added 35 dropwise while maintaining the tamper~ture below 15C. After the addition~ were complete, chlorine, chlorine ~0.10 mola) was added via a gas inlet tube and the reaction was heated ~75;~ ~
to reflux. Maltol was i~olated ~rom the cooled solution by the procedure of Example 1.
3(6H)-one _.
S To a solution of 25 g of 1(2 furyl)-l-ethanol in 125 ml of tetrahydrofuran and 125 ml of water at 5C. was added 1 equivalent of bromine. The temperatur~ was main-tained at 5 to 10~C. throughout the addition. The solu-tion was adjusted to pH 2.1 and extracted with ethyl acetate t3 X 50 ml). The ethyl acetate extract was dried and evapo-rated to give a yellow oil. The oil was chromatographed on a silica gel and eluted with chloroform-ethyl acetate ~3:1) to give 4.8 g of clear oil which was shown by spectral data to be identical with 6-hydroxy 2-methyl-2H-pyran-3(6H)-one lS prepared from 6-methoxy-2-methyl-2H~pyran-3(6H)-one by acid hydrolysis [Tetrahedron 27, 1973~1971)].
IR ~CHC13) 3700, 3300, 1700 cm~l NMR ~CDC13~): 6.8-7.1 ~lH, d of d); 6.0~6.2 ~lH, d), 5~6 ~lH, br. s, exchanges with D2O); 5.4-5.5 ~lH, d);
S To a solution of 25 g of 1(2 furyl)-l-ethanol in 125 ml of tetrahydrofuran and 125 ml of water at 5C. was added 1 equivalent of bromine. The temperatur~ was main-tained at 5 to 10~C. throughout the addition. The solu-tion was adjusted to pH 2.1 and extracted with ethyl acetate t3 X 50 ml). The ethyl acetate extract was dried and evapo-rated to give a yellow oil. The oil was chromatographed on a silica gel and eluted with chloroform-ethyl acetate ~3:1) to give 4.8 g of clear oil which was shown by spectral data to be identical with 6-hydroxy 2-methyl-2H-pyran-3(6H)-one lS prepared from 6-methoxy-2-methyl-2H~pyran-3(6H)-one by acid hydrolysis [Tetrahedron 27, 1973~1971)].
IR ~CHC13) 3700, 3300, 1700 cm~l NMR ~CDC13~): 6.8-7.1 ~lH, d of d); 6.0~6.2 ~lH, d), 5~6 ~lH, br. s, exchanges with D2O); 5.4-5.5 ~lH, d);
4.8-5.0 (lH, q); 1.3-1~6~3H, t).
The method of Example 13 was repeated with a furfuryl alcohol of khe formula ~ OH
O ~
R
to yield a compound of the formula ~0 HO o R
wherein R is hydrogen or ethyl.
Eth~l compound: IR ~CHC13) 3600, 3340, 1706 cm 1 30 Hydro ~ : IR (CHC13) 3565,3300, 1703 cm 1 ~7~
Exd~ 15 4-Br o ~ -2-meth~ ~H~ ~
To a solutiorl of 25 g o~ 1(2-furyl)-1-ethanol in 125 ml of tetrahydrofuran and 125 ~1 of water at 0 to 5C.
was added dropwise 2.2 equivalent--3 of bromine. Throughout the addi'cion the temperakure was maintained at 5 to 10C.
After the bromine addition the solution ~as stirred at room temperature for 30 minutes and the pH adjusted to 2.1 with 2N NaOH solution. The reaction mixture was extracted with ethyl acetate (3 X 100 ml3. The ethyl acetate extracts were combined, dried over MgSO~, filtered and taken to dry-ness. The residue was chromatographed on silica gel and eluted with chloroform~ethyl acetate ~95:5). The product was an orange oil which was rechromatographed on silica gel and eluted with chloroform-ethyl acetate (95:5).
NMR ~CDC13,~) 7.3 (lH, d); 5.6 (lH,d); 4.7-5.0 ~ lH, q~; 1.1-1.5 (3H, m).
The procadure of Example 15 was repeated with a furfuryl alcohol of the formula r--to yield a compound of the formula ",[~
HO O R
wherein R is hydrogen or ethyl.
4-bromo-6-hydroxy-2-ethyl-2H-pyran-3~H)-one NMR (CDC13,~) 7.4 (lH, d); 4.6-4.9 ~lH, m); 1.3-2.2 (2H, m); 1.0-1.3 (3H, t).
Hydrogen compound 4-bromo-6-hydroxy-2H=pyran-3(6H) 7.4 (lH, d); 5.5 (lH, d); 406 ~2H, d of d)~
Example 17 A solution of 4-bromo-6-hydroxy 2-methyl-2H-pyran-3(6H)-one was prepared by dissolving the compound in either an aqueous inorganic or aqueous organic acidO
The solution was then heated to re~lux, cooled to room temperat~re, khe pH adjusted to 2.1 with 6 N NaOH and the 75~ ~
reaction mixture extracted with chloroform. Concentration yielded mal~ol. The aclds, time of reaction and yields of maltol were as follows:
Acid concentration~%l P~eac~ion Time ~Ers.) Yield~%~
The method of Example 13 was repeated with a furfuryl alcohol of khe formula ~ OH
O ~
R
to yield a compound of the formula ~0 HO o R
wherein R is hydrogen or ethyl.
Eth~l compound: IR ~CHC13) 3600, 3340, 1706 cm 1 30 Hydro ~ : IR (CHC13) 3565,3300, 1703 cm 1 ~7~
Exd~ 15 4-Br o ~ -2-meth~ ~H~ ~
To a solutiorl of 25 g o~ 1(2-furyl)-1-ethanol in 125 ml of tetrahydrofuran and 125 ~1 of water at 0 to 5C.
was added dropwise 2.2 equivalent--3 of bromine. Throughout the addi'cion the temperakure was maintained at 5 to 10C.
After the bromine addition the solution ~as stirred at room temperature for 30 minutes and the pH adjusted to 2.1 with 2N NaOH solution. The reaction mixture was extracted with ethyl acetate (3 X 100 ml3. The ethyl acetate extracts were combined, dried over MgSO~, filtered and taken to dry-ness. The residue was chromatographed on silica gel and eluted with chloroform~ethyl acetate ~95:5). The product was an orange oil which was rechromatographed on silica gel and eluted with chloroform-ethyl acetate (95:5).
NMR ~CDC13,~) 7.3 (lH, d); 5.6 (lH,d); 4.7-5.0 ~ lH, q~; 1.1-1.5 (3H, m).
The procadure of Example 15 was repeated with a furfuryl alcohol of the formula r--to yield a compound of the formula ",[~
HO O R
wherein R is hydrogen or ethyl.
4-bromo-6-hydroxy-2-ethyl-2H-pyran-3~H)-one NMR (CDC13,~) 7.4 (lH, d); 4.6-4.9 ~lH, m); 1.3-2.2 (2H, m); 1.0-1.3 (3H, t).
Hydrogen compound 4-bromo-6-hydroxy-2H=pyran-3(6H) 7.4 (lH, d); 5.5 (lH, d); 406 ~2H, d of d)~
Example 17 A solution of 4-bromo-6-hydroxy 2-methyl-2H-pyran-3(6H)-one was prepared by dissolving the compound in either an aqueous inorganic or aqueous organic acidO
The solution was then heated to re~lux, cooled to room temperat~re, khe pH adjusted to 2.1 with 6 N NaOH and the 75~ ~
reaction mixture extracted with chloroform. Concentration yielded mal~ol. The aclds, time of reaction and yields of maltol were as follows:
Acid concentration~%l P~eac~ion Time ~Ers.) Yield~%~
5 HCl i~
EICl 32 S S2 HCl 18 5 35 HCl 25 3 49 HBr 18 5 24 CF3COO~ neat 3 36 ~NO3 35 3 0'4 15 CF3COO~ neat 3 70 CH3COOH neat 3 77 HCOOH neat 3 24 2 4 Alternatively organic solvent3 such as benzene and toluene, together with acidic materials such as p-toluenesulfon-ic acid and "Am~erlite"* IR-12~, may be used.
Example 18 Tha method of Example lS was repeated employing chlorine in place of bromine and the appropria~e furfuryl alco-hols to produce the following compounds:
M ~ : 4-chloro-6-hydroXy.-2-methyl~ pyran-3(6H~-one NMR ~CDCl ,~1: 7.1 ~lH,d~: 5.8 ~lH,d):
4.6-5.0 (lH,m~; 4.4 ~lH, br.s.~; 1.2-1.5 ~3H,m).
~ : 4-chloro-6~hydroxy-2-ethyl-2H-pyran-3(6H)-3Q one NMR ~CDC13,~): 7.~7.1 ~lH,d); 5.6-
EICl 32 S S2 HCl 18 5 35 HCl 25 3 49 HBr 18 5 24 CF3COO~ neat 3 36 ~NO3 35 3 0'4 15 CF3COO~ neat 3 70 CH3COOH neat 3 77 HCOOH neat 3 24 2 4 Alternatively organic solvent3 such as benzene and toluene, together with acidic materials such as p-toluenesulfon-ic acid and "Am~erlite"* IR-12~, may be used.
Example 18 Tha method of Example lS was repeated employing chlorine in place of bromine and the appropria~e furfuryl alco-hols to produce the following compounds:
M ~ : 4-chloro-6-hydroXy.-2-methyl~ pyran-3(6H~-one NMR ~CDCl ,~1: 7.1 ~lH,d~: 5.8 ~lH,d):
4.6-5.0 (lH,m~; 4.4 ~lH, br.s.~; 1.2-1.5 ~3H,m).
~ : 4-chloro-6~hydroxy-2-ethyl-2H-pyran-3(6H)-3Q one NMR ~CDC13,~): 7.~7.1 ~lH,d); 5.6-
6.0 ~2H,~); 4.4-5.0 ~l~,m~; 1.6-2.1 ~2H, m); Q.9~ 3H,t).
4-chloro~6~hydr~xy-2H-pyran-3(6~)-one NMR
~CDC13,~): 7.1~7.2 ~lH,d); 5.6 (lH,d); 4.4-4.9 ~2H,d o~ d) ~D2O added).
The method of Example lS wa~ repeated to yield a compound of the formula * Trade Mark ~7~
-2~-X
HO ~ O ~ R
wherein R is propyl, butyl, phenyl or benzyl; X is bromine or chlorine.
4-Bromo-6-hydroxy-2-methyl-2H-pyran-3~6H)-ona was heated under vacuum for 16 hours at 40C. The resulting oily solid was crystallized from isopropyl alcohol ~o yiald 6,6'-oxybis [4-bromo-2-methyl-2~-pyran-3(6~)-one], m~p. .
125C.
~
The method of Example 20 was repeated starting with a compound o~ the formula X
_~i~' HO o~R
to yield a compound of the Eormula X X
R o O R
wheréin R is hydrogen, ethyl, propyl~ butyl, phenyl or benzyl; X is bromine or chlorine.
R X M,P. ~C.) CH3 Cl 177 to 179 CH2CH3 Cl 132 to 135 Exa ~
A solution of 4-bromo-6-hydroxy-2-methyl 2H-pyran-3~6H)-one ~0,0025 mole) in 20 ml of 35~ phosphoric acid was refluxed for about 5 hours. Maltol (34%) was isolated by the procedure of Example 1.
4-chloro~6~hydr~xy-2H-pyran-3(6~)-one NMR
~CDC13,~): 7.1~7.2 ~lH,d); 5.6 (lH,d); 4.4-4.9 ~2H,d o~ d) ~D2O added).
The method of Example lS wa~ repeated to yield a compound of the formula * Trade Mark ~7~
-2~-X
HO ~ O ~ R
wherein R is propyl, butyl, phenyl or benzyl; X is bromine or chlorine.
4-Bromo-6-hydroxy-2-methyl-2H-pyran-3~6H)-ona was heated under vacuum for 16 hours at 40C. The resulting oily solid was crystallized from isopropyl alcohol ~o yiald 6,6'-oxybis [4-bromo-2-methyl-2~-pyran-3(6~)-one], m~p. .
125C.
~
The method of Example 20 was repeated starting with a compound o~ the formula X
_~i~' HO o~R
to yield a compound of the Eormula X X
R o O R
wheréin R is hydrogen, ethyl, propyl~ butyl, phenyl or benzyl; X is bromine or chlorine.
R X M,P. ~C.) CH3 Cl 177 to 179 CH2CH3 Cl 132 to 135 Exa ~
A solution of 4-bromo-6-hydroxy-2-methyl 2H-pyran-3~6H)-one ~0,0025 mole) in 20 ml of 35~ phosphoric acid was refluxed for about 5 hours. Maltol (34%) was isolated by the procedure of Example 1.
7~
E~
A compound of the formula X X
Oq~ ~0 RJ~o ~o~O~'R
wherein R is hydrogen, methyl, ethyl, propyl, butyl/ phenyl or benzyl; and X is bromine or chlorine is treated by the method of Example 22 ~o yield a compound of the formula ~OH
O R
wherein R is as defined above.
~, A solution of 6~methoxy-2-methyl-2H-pyran-3(6H)-one ~0.01 mole) in 20 ml of acetic acid was treated with gaseous chlorine ~0.01 mole~ at room temperature. The reaction mixtuxe was then heated to reflux for about.one hour, cooled to room temperature, diluted with 20 ml of water, khe p~I adjusted with 50% NaOH solution to 7.0 and the reaction mixture extracted with chloroform~ The chloroform extrac~ was concentrated to yield maltol w~ich was recrystal-lized ~rom methanol to give the pure product 156%), m.p.
2~ 159.5 to 160.5C.
ThP procedure of Example 24 was repeated starting with a compound of the formula ~0 R'O ~ O ~ R
wherein R is hydroge~, alXyl of 2 to 4 carbon atoms, phenyl or benzyl; Rl is alkyl of 2 to 4 carbon atoms or -COR"
where R" is methyl, ethyl or phenyl to yield a gamma-pyrone ~7~
of the formula o ¢~OH
wherain R is hydrogen, alkyl of 2 to 4 carbon atorn~, phenyl or benzyl.
Example 26 The procedure of Example 24 was repeated with com-parable results replacing acetic acid with each of the fol lowing solvents:
formic acid methanol ethanol tetrahydrofuran' benæene ethylene glycol trifluoracetic acid acetone acetonitrile Example 27 The procedure of Example 24 was repeated with com-parable results replacing chlorine with bromine, sodium or potassium hypochlorite or hypobromite, gaseous bromine chlor-~0 ide or bromine chloride prepared in situ by the addition of chlorine to a solution containing sodium bromide or bromine to a solution of sodium chloride.
Exarnple 28 4-chloro-6-methox~2~methyl-_~ Ey~--3(6H)-one To a solution of 6-methoxy-2-methyl-2H-pyran-3(6H)-one ~0.05 mol ) in 70 ml of dichloromethane at -10C. was added chlorine ~0.05 mole) via a gas inlet tube. Following this addition, triethylamine (0.05 mole) was added slowly while maintaining the tempe~ature at -10C. after 30 minutes of stirring the reaction mixture was allowed to warm to room temperature, filtered to remove tri~thylamin~ hydro-chloride and the solvent removed under vacuum. Redissolving the crude product in ether-benæene and filtration removed the last traces of triethylamine hydrochloride. Removal ~7~5~1 of the solvent gave 4-chloro-6-methoxy-2-meth~1-2H-3(6H)-one (yield, 99%)~ NMR analysis of the signals at 5.05 to 5.25 clearly showed two doublets in a 3 to 1 ratio cor~e~ponding to the proton at C-6 of the two possible isomers of the com-pound. Both optic~l forms of the krans isomer had beensynthesized from ~ carbohydrate precursor by Paulsen, Eberstein and Koebernick, Tetrahedron Letters ~377 (1974~.
Exam~le 29 4-Bromo-6-metho~y-2-meth~-2H-~yran-3(6H)-one The procedure of Example 28 was repeated replacing chlorine with bromine to obtain 4-bromo-6-methoxy-2-methyl-2H-pyran~3t6H)-one in 93% yield. The two optical forms of the trans isomer had been synthesized by Paulsen and co-workers, Tetrahedron Letters 4377 (1974).
~
The procedure of Examples 28 and 29, respeotively, was repeated starting with a compound of the formula:
~0 R'~o j~R
wherein R is hydrogen, alkyl of 2 to 4 carbon atoms, phenyl or benzyl; and R' is alkyl of 2 to 4 carbon atoms to yield a compound o the formula X
~0 RlO~\o~ - R
wherein R and R' are as defined above; and X is chlorine or bromine.
~
4-B~omo-6-acetyl-2H-~Yran-3~6H)-one A solution in dichloromethane of 6-acetyl-2H~
pyran-3~6H)-one, prepared by the method described in Tetra-hedron 27, 1973 ~1971), was hromina~ed by the procedure of Example 6 to yield 4-bromo-6-acetyl-2~-pyran-3~6H)-one, m.p, -2~-78 to 80C. The mass spactru~ of the compound showed the expected parent peaks at 234 and 236 mass units.
~559~e=~ 3~0o~Y~ one The procedure of Example 31 was repeated with 6-acetyl~2-methyl-2M-pyran-3(6H)~one to yield 4-bromo-6-acetyl-2-methyl-2H-3~6~-one which showed parent masses of 249.96 and 247.96 by mass spectroscopy and the following NMR
spectrum: ~, CDC13); 7.3(1H, d); 6.4(1H, d of d); 4.7(1H, Q); 2.2 ~3H, S~; 1.4(3H, S).
Exam~le 33 The procedure of Example 28 was repeated employ-ing chlorine in place of bxomine and starting with a com-pound of the formula:
lS f ~
R O O ~ ~
wherein R is hydrogen, alkyl of 1 to 4 carbon atom~, phenyl or benzyl, R' is alkyl of 1 to 4 carbon atoms or -COR"
where Rl is methyl, ethyl or phenyl to yield a compound of the formula:
X
2~ ,O
R'O O R
wherein R and R' are as defined aboye and X is chlorine.
Ex~ e 34 To a round bottom flask equipped with a stirring bar and a aondenser was added 4-chloro-6-methoxy~2-methyl-2H-pyran-3~6H)-one and ac~ti~ acid and the reaction mixture heated to reflux for an hour. Maltol (65%) was obtained on cooling.
The procedure of Example 34 was repeated with com~
par~bla resul~s using formic acid in place af acetic acid 7~1 The proc~dure of Example 34 was repeated starting with a compound of the formula:
X
R ~ o~\ o/l--R
S wherein R is hydrogen, alkyl of 1 to 4 carbon atoms, phenyl or benzyl; R' is alkyl of 1 to 4 carbon atoms or -COR"
where R" is methyl, ethyl or phenyli and X is bromine or chlorine to yield a compound of the formula:
o OH
O
lQ wherein R is hydrogen, alkyl of 1 to 4 carbon atoms, phenyl or ben~yl.
Example 37 6-~thyl-2-ethyl-3-h~~g~y~ y~----4 one In a three necked round bottom flask were added lS 28 ml of methanol and 38 ml of water. The solution was cooled to -15C. and 0.166 mole of 5-methyl-2-(2-hydroxy-propyl)furan (J. Org. Chem., 26, 1673 1960) and 0.416 mole of chlorine were added simultaneously. During the addi~ion, the temperature was maintained between -16 and -8C. When addition was completed, the solution was warmed to 80C.
and refluxed for about 3 hours. Upon cooling to room temp-erature, the p~ was adjusted to 2.1 and the mixture extract-ed with chloroform (3 x 100 ml). The combined oryanic layers were washed with water, brine and dried over rnagn~-sium sulfate. The organic solution was filtered and evapor~ated to give a thick dark solid. The solid was recrystallized ~wice from methanol to give 8006 grams (30% yield) of white solid. Sublimation yielded pur~ product, m.p. 157 to 159Co Analysis Calc'd. for C8H1003: C, 62.33; H, 6.54 -~6~
Found: C, 62.U5; H, 6.44 NMR ~CDC13,~; 6-CH , 2~33 (3H, 5); 2~CH3, 1.30 ~3H, t);
2-CH2-, 2.75 (2H, q~artet), 5H, 6.23 ~lH, s).
2,6-~imet~yl-3~hydrox~y 4~I~pyran-4-one In a three necked round bottom flask were added 28 ml of water and 32 ml of methanol and the mixture was cooled to -15C. The solution was treated with 0.167 mole of 5-methyl~2 ~-hydroxy-ethyl)furan (~. Org. Chem., 26, 1673, 1960) and 0.416 mole of chlorine simultaneously. The temperature was maintained at -15 to -10C. during addition.
The mixture was allowed to warm to room tempexature over 30 minutes and heated to reflux for 3 hours. The cooled solution was adjusted to pH 2.1 and extracted with chloro-form ~3 X 100 ml). The chloroform extracts were combined,washed with ~ater and brine, dried over magnesium sulfate, filtered and evaporated. The residue, a dark oil, was chromatographed on silica gel developed with methylene chloride/ethyl acetate (95:5). The product, isolated by evaporation, was recrystallized from methanol as a tan solid ~yield, 25%~. Sublimation yielded white crystals, m.p. 161 to 163~C.
Analysis Calc d. for C7H8O2: C, .99; H, 5.75 Found; C, 59.83; H, 5.82 NMR ~CDCl3,~); 5-CH3, 2.33 (3H, s); 2-CH3, 2~26 (3H, s);
5-H, 6.10 ~lH, s).
E~
A compound of the formula X X
Oq~ ~0 RJ~o ~o~O~'R
wherein R is hydrogen, methyl, ethyl, propyl, butyl/ phenyl or benzyl; and X is bromine or chlorine is treated by the method of Example 22 ~o yield a compound of the formula ~OH
O R
wherein R is as defined above.
~, A solution of 6~methoxy-2-methyl-2H-pyran-3(6H)-one ~0.01 mole) in 20 ml of acetic acid was treated with gaseous chlorine ~0.01 mole~ at room temperature. The reaction mixtuxe was then heated to reflux for about.one hour, cooled to room temperature, diluted with 20 ml of water, khe p~I adjusted with 50% NaOH solution to 7.0 and the reaction mixture extracted with chloroform~ The chloroform extrac~ was concentrated to yield maltol w~ich was recrystal-lized ~rom methanol to give the pure product 156%), m.p.
2~ 159.5 to 160.5C.
ThP procedure of Example 24 was repeated starting with a compound of the formula ~0 R'O ~ O ~ R
wherein R is hydroge~, alXyl of 2 to 4 carbon atoms, phenyl or benzyl; Rl is alkyl of 2 to 4 carbon atoms or -COR"
where R" is methyl, ethyl or phenyl to yield a gamma-pyrone ~7~
of the formula o ¢~OH
wherain R is hydrogen, alkyl of 2 to 4 carbon atorn~, phenyl or benzyl.
Example 26 The procedure of Example 24 was repeated with com-parable results replacing acetic acid with each of the fol lowing solvents:
formic acid methanol ethanol tetrahydrofuran' benæene ethylene glycol trifluoracetic acid acetone acetonitrile Example 27 The procedure of Example 24 was repeated with com-parable results replacing chlorine with bromine, sodium or potassium hypochlorite or hypobromite, gaseous bromine chlor-~0 ide or bromine chloride prepared in situ by the addition of chlorine to a solution containing sodium bromide or bromine to a solution of sodium chloride.
Exarnple 28 4-chloro-6-methox~2~methyl-_~ Ey~--3(6H)-one To a solution of 6-methoxy-2-methyl-2H-pyran-3(6H)-one ~0.05 mol ) in 70 ml of dichloromethane at -10C. was added chlorine ~0.05 mole) via a gas inlet tube. Following this addition, triethylamine (0.05 mole) was added slowly while maintaining the tempe~ature at -10C. after 30 minutes of stirring the reaction mixture was allowed to warm to room temperature, filtered to remove tri~thylamin~ hydro-chloride and the solvent removed under vacuum. Redissolving the crude product in ether-benæene and filtration removed the last traces of triethylamine hydrochloride. Removal ~7~5~1 of the solvent gave 4-chloro-6-methoxy-2-meth~1-2H-3(6H)-one (yield, 99%)~ NMR analysis of the signals at 5.05 to 5.25 clearly showed two doublets in a 3 to 1 ratio cor~e~ponding to the proton at C-6 of the two possible isomers of the com-pound. Both optic~l forms of the krans isomer had beensynthesized from ~ carbohydrate precursor by Paulsen, Eberstein and Koebernick, Tetrahedron Letters ~377 (1974~.
Exam~le 29 4-Bromo-6-metho~y-2-meth~-2H-~yran-3(6H)-one The procedure of Example 28 was repeated replacing chlorine with bromine to obtain 4-bromo-6-methoxy-2-methyl-2H-pyran~3t6H)-one in 93% yield. The two optical forms of the trans isomer had been synthesized by Paulsen and co-workers, Tetrahedron Letters 4377 (1974).
~
The procedure of Examples 28 and 29, respeotively, was repeated starting with a compound of the formula:
~0 R'~o j~R
wherein R is hydrogen, alkyl of 2 to 4 carbon atoms, phenyl or benzyl; and R' is alkyl of 2 to 4 carbon atoms to yield a compound o the formula X
~0 RlO~\o~ - R
wherein R and R' are as defined above; and X is chlorine or bromine.
~
4-B~omo-6-acetyl-2H-~Yran-3~6H)-one A solution in dichloromethane of 6-acetyl-2H~
pyran-3~6H)-one, prepared by the method described in Tetra-hedron 27, 1973 ~1971), was hromina~ed by the procedure of Example 6 to yield 4-bromo-6-acetyl-2~-pyran-3~6H)-one, m.p, -2~-78 to 80C. The mass spactru~ of the compound showed the expected parent peaks at 234 and 236 mass units.
~559~e=~ 3~0o~Y~ one The procedure of Example 31 was repeated with 6-acetyl~2-methyl-2M-pyran-3(6H)~one to yield 4-bromo-6-acetyl-2-methyl-2H-3~6~-one which showed parent masses of 249.96 and 247.96 by mass spectroscopy and the following NMR
spectrum: ~, CDC13); 7.3(1H, d); 6.4(1H, d of d); 4.7(1H, Q); 2.2 ~3H, S~; 1.4(3H, S).
Exam~le 33 The procedure of Example 28 was repeated employ-ing chlorine in place of bxomine and starting with a com-pound of the formula:
lS f ~
R O O ~ ~
wherein R is hydrogen, alkyl of 1 to 4 carbon atom~, phenyl or benzyl, R' is alkyl of 1 to 4 carbon atoms or -COR"
where Rl is methyl, ethyl or phenyl to yield a compound of the formula:
X
2~ ,O
R'O O R
wherein R and R' are as defined aboye and X is chlorine.
Ex~ e 34 To a round bottom flask equipped with a stirring bar and a aondenser was added 4-chloro-6-methoxy~2-methyl-2H-pyran-3~6H)-one and ac~ti~ acid and the reaction mixture heated to reflux for an hour. Maltol (65%) was obtained on cooling.
The procedure of Example 34 was repeated with com~
par~bla resul~s using formic acid in place af acetic acid 7~1 The proc~dure of Example 34 was repeated starting with a compound of the formula:
X
R ~ o~\ o/l--R
S wherein R is hydrogen, alkyl of 1 to 4 carbon atoms, phenyl or benzyl; R' is alkyl of 1 to 4 carbon atoms or -COR"
where R" is methyl, ethyl or phenyli and X is bromine or chlorine to yield a compound of the formula:
o OH
O
lQ wherein R is hydrogen, alkyl of 1 to 4 carbon atoms, phenyl or ben~yl.
Example 37 6-~thyl-2-ethyl-3-h~~g~y~ y~----4 one In a three necked round bottom flask were added lS 28 ml of methanol and 38 ml of water. The solution was cooled to -15C. and 0.166 mole of 5-methyl-2-(2-hydroxy-propyl)furan (J. Org. Chem., 26, 1673 1960) and 0.416 mole of chlorine were added simultaneously. During the addi~ion, the temperature was maintained between -16 and -8C. When addition was completed, the solution was warmed to 80C.
and refluxed for about 3 hours. Upon cooling to room temp-erature, the p~ was adjusted to 2.1 and the mixture extract-ed with chloroform (3 x 100 ml). The combined oryanic layers were washed with water, brine and dried over rnagn~-sium sulfate. The organic solution was filtered and evapor~ated to give a thick dark solid. The solid was recrystallized ~wice from methanol to give 8006 grams (30% yield) of white solid. Sublimation yielded pur~ product, m.p. 157 to 159Co Analysis Calc'd. for C8H1003: C, 62.33; H, 6.54 -~6~
Found: C, 62.U5; H, 6.44 NMR ~CDC13,~; 6-CH , 2~33 (3H, 5); 2~CH3, 1.30 ~3H, t);
2-CH2-, 2.75 (2H, q~artet), 5H, 6.23 ~lH, s).
2,6-~imet~yl-3~hydrox~y 4~I~pyran-4-one In a three necked round bottom flask were added 28 ml of water and 32 ml of methanol and the mixture was cooled to -15C. The solution was treated with 0.167 mole of 5-methyl~2 ~-hydroxy-ethyl)furan (~. Org. Chem., 26, 1673, 1960) and 0.416 mole of chlorine simultaneously. The temperature was maintained at -15 to -10C. during addition.
The mixture was allowed to warm to room tempexature over 30 minutes and heated to reflux for 3 hours. The cooled solution was adjusted to pH 2.1 and extracted with chloro-form ~3 X 100 ml). The chloroform extracts were combined,washed with ~ater and brine, dried over magnesium sulfate, filtered and evaporated. The residue, a dark oil, was chromatographed on silica gel developed with methylene chloride/ethyl acetate (95:5). The product, isolated by evaporation, was recrystallized from methanol as a tan solid ~yield, 25%~. Sublimation yielded white crystals, m.p. 161 to 163~C.
Analysis Calc d. for C7H8O2: C, .99; H, 5.75 Found; C, 59.83; H, 5.82 NMR ~CDCl3,~); 5-CH3, 2.33 (3H, s); 2-CH3, 2~26 (3H, s);
5-H, 6.10 ~lH, s).
Claims (9)
- The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:
i. A process for preparing a compound of the formula:
...(II) wherein R is hydrogen, alkyl of 1 to 4 carbon atoms, phenyl or benzyl, R' is hydrogen, alkyl of 1 to 4 carbon atoms, or -COR", wherein R" is methyl, ethyl or phenyl, R''' is hydrogen or alkyl of 1 to 4 carbon atoms and X is chlorine or bromine, which comprises either (a) when R' is hydrogen, alkyl of 1 to 4 carbon atoms or -COR", wherein R" is as defined above, and R, R''' and X are as defined above, reacting a compound of the formula:
...(IV) wherein R, R' and R''' are as defined above, in a solvent at a temperature of -50° to 50°C. with at least one equivalent of a halogen-containing oxidant selected from chlorine, bromine, bromine chloride, hypochlorous acid, hypobromous acid or mixtures thereof until the reaction is substantially complete; or (b) when R' is hydrogen and R, R''' and X are as defined above, reacting a compound of the formula:
...(III) Where R and R''' are as defined above, in an aqueous solvent at a temperature of -50° to 50°C. with at least two equivalents of a halogen-containing oxidant selected from chlorine, bromine, bromine chloride, hypochlorous acid, hypobromous acid or mixtures thereof until the reaction is substantially complete. - 2. A process according to claim l, wherein the solvent used in reaction (a) is water, an alkanol or diol of 1 to 4 carbon atoms, an ether of 2 to 10 carbon atoms, or a low molecular weight ketone, nitrile, ester or amide.
- 3. A process according co claim l, wherein reaction (b) is conducted in the presence of a co-solvent which is an alkanol or diol of 1 to 4 carbon atoms, an ether of 2 to 10 carbon atoms, or a low molecular weight ketone, nitrile, ester or amide.
- 4. A process according to claim 1, wherein R is ethyl and R' is alkyl of 1 to 4 carbon atoms or -COR" wherein R" is methyl, ethyl or phenyl, and R''' and X are as defined in claim 1.
- 5. A compound of the formula:
(II) wherein R is hydrogen, alkyl of 1 to 4 carbon atoms, phenyl or benzyl, R' is hydrogen, alkyl of 1 to 4 carbon atoms or -COR", wherein R" is methyl, ethyl or phenyl, R''' is hydrogen or alkyl of 1 to 4 carbon atoms and X is chloro or bromo, provided that (i) when R' is alkyl of 1 to 4 carbon atoms or -COR", R is ethyl; and (ii) when X is chlorine, R' is ethyl and R is ethyl, R''' is not hydrogen. - 28 (6). A compound according to claim 5 of the formula:
. . . (VI) wherein R' is alkyl of 1 to 4 carbon atoms or -COR" wherein R" is methyl, ethyl or phenyl, R''' is hydrogen or alkyl of 1 to 4 carbon atoms and X is chlorine or bromine, provided that when X is chlorine and R' is ethyl, R''' is not hydrogen. - 7. A compound according to claim 6 of the formula:
. . . (II') wherein R is hydrogen, alkyl of 1 to 4 carbon atoms, phenyl or benzyl, R''' is hydrogen or alkyl of 1 to 4 carbon atoms and X
is chlorine or bromine. - 8. A process according to claim 1 for preparing a compound of the formula:
. . . (II') wherein R is hydrogen, alkyl of 1 to 4 carbon atoms, phenyl or benzyl, R''' is hydrogen or alkyl of 1 to 4 carbon atoms and X is chlorine or bromine, which comprises reacting a compound of the formula:
...(III) wherein R and R''' are as defined above, in an aqueous solvent at a temperature of -50° to 50°C. with at least two equivalents of a halogen-containing oxidant selected from chlorine, bromine, bromine chloride, hypochlorous acid, hypobromous acid or mixtures thereof until the reaction is substantially complete. - 9. The process as in claim 1, 2 or 4, wherein alternative (a) is employed.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US71090176A | 1976-08-02 | 1976-08-02 | |
| US710,901 | 1976-08-02 | ||
| US05/721,885 US4082717A (en) | 1976-08-02 | 1976-09-09 | Preparation of gamma-pyrones |
| US721,885 | 1985-04-11 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1117541A true CA1117541A (en) | 1982-02-02 |
Family
ID=27108548
Family Applications (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA279,922A Expired CA1095921A (en) | 1976-08-02 | 1977-06-06 | Preparation of gamma-pyrones |
| CA363,273A Expired CA1110254A (en) | 1976-08-02 | 1980-10-24 | Preparation of gamma-pyrones |
| CA000363274A Expired CA1117541A (en) | 1976-08-02 | 1980-10-24 | 4-halo-dihydropyrans and the preparation thereof |
Family Applications Before (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA279,922A Expired CA1095921A (en) | 1976-08-02 | 1977-06-06 | Preparation of gamma-pyrones |
| CA363,273A Expired CA1110254A (en) | 1976-08-02 | 1980-10-24 | Preparation of gamma-pyrones |
Country Status (36)
| Country | Link |
|---|---|
| JP (7) | JPS5318578A (en) |
| AR (1) | AR216080A1 (en) |
| AT (3) | AT362790B (en) |
| BE (1) | BE855965A (en) |
| BG (4) | BG28989A4 (en) |
| BR (1) | BR7703970A (en) |
| CA (3) | CA1095921A (en) |
| CH (4) | CH625798A5 (en) |
| CS (3) | CS203921B2 (en) |
| DD (1) | DD132494A5 (en) |
| DE (3) | DE2728499C2 (en) |
| DK (4) | DK153483C (en) |
| EG (1) | EG13080A (en) |
| ES (5) | ES459994A1 (en) |
| FI (6) | FI72722C (en) |
| FR (1) | FR2372821A1 (en) |
| GB (5) | GB1538375A (en) |
| GR (1) | GR68938B (en) |
| HK (5) | HK30481A (en) |
| HU (4) | HU185687B (en) |
| IE (5) | IE45643B1 (en) |
| IT (1) | IT1106258B (en) |
| LU (1) | LU77600A1 (en) |
| MX (1) | MX4597E (en) |
| MY (3) | MY8100267A (en) |
| NL (5) | NL170955C (en) |
| NO (7) | NO150561C (en) |
| NZ (1) | NZ184342A (en) |
| PH (5) | PH13557A (en) |
| PL (4) | PL115586B1 (en) |
| PT (1) | PT66694B (en) |
| RO (4) | RO78951A2 (en) |
| SE (6) | SE433079B (en) |
| SU (2) | SU955859A3 (en) |
| TR (1) | TR19652A (en) |
| YU (4) | YU40166B (en) |
Families Citing this family (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1095921A (en) * | 1976-08-02 | 1981-02-17 | Thomas M. Brennan | Preparation of gamma-pyrones |
| JPS5444675A (en) * | 1977-09-12 | 1979-04-09 | Shin Etsu Chem Co Ltd | Production of 3-hydroxy-4-pyrone analog |
| FR2402654A1 (en) * | 1977-09-12 | 1979-04-06 | Shinetsu Chemical Co | Tetra:hydro-pyranone derivs. - useful as intermediates for cpds. used as food flavours |
| JPS5741226U (en) * | 1980-08-20 | 1982-03-05 | ||
| JPS59135008U (en) * | 1983-02-28 | 1984-09-10 | 松下電工株式会社 | Distribution board device |
| JPS6050245A (en) * | 1983-08-29 | 1985-03-19 | Nissan Motor Co Ltd | Fuel injection device in internal-combustion engine |
| JPH0226945Y2 (en) * | 1985-09-11 | 1990-07-20 | ||
| JP2586607B2 (en) * | 1987-10-30 | 1997-03-05 | 日産化学工業株式会社 | Production method of optically active alcohol |
| WO2008116301A1 (en) | 2007-03-28 | 2008-10-02 | Apotex Technologies Inc. | Fluorinated derivatives of deferiprone |
| WO2009129592A1 (en) | 2008-04-25 | 2009-10-29 | Apotex Technologies Inc. | Liquid formulation for deferiprone with palatable taste |
| ME01911B (en) | 2009-07-03 | 2014-12-20 | Apotex Tech Inc | Fluorinated derivatives of 3-hydroxypyridin-4-ones |
| WO2017168309A1 (en) * | 2016-03-29 | 2017-10-05 | Dr. Reddy’S Laboratories Limited | Process for preparation of eribulin and intermediates thereof |
| CN108609456B (en) * | 2016-12-13 | 2021-03-12 | 奥的斯电梯公司 | Openable expansion panel and elevator suspended ceiling, elevator car and elevator system with same |
| CN111606879A (en) * | 2020-05-25 | 2020-09-01 | 安徽金禾实业股份有限公司 | Method for preparing 2-hydroxymethyl-3-alkoxy-4H-pyran-4-ketone by one-pot method |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3491122A (en) * | 1966-09-14 | 1970-01-20 | Monsanto Co | Synthesis of 4-pyrones |
| US3547912A (en) * | 1968-07-29 | 1970-12-15 | American Home Prod | Derivatives of 2h-pyran-3(6h)-ones and preparation thereof |
| JPS5145565B1 (en) * | 1968-10-12 | 1976-12-04 | ||
| US3621063A (en) * | 1968-12-24 | 1971-11-16 | Monsanto Co | Unsaturated acyclic ketones |
| US3832357A (en) * | 1971-05-26 | 1974-08-27 | Daicel Ltd | Process for preparation of 3-hydroxy-2-alkyl-4-pyrone |
| JPS5212166A (en) * | 1975-07-17 | 1977-01-29 | Tatsuya Shono | Process for preparation of 4-pyron derivatives |
| IE42789B1 (en) * | 1975-08-28 | 1980-10-22 | Pfizer | Preparation of gamma-pyrones |
| CA1095921A (en) * | 1976-08-02 | 1981-02-17 | Thomas M. Brennan | Preparation of gamma-pyrones |
-
1977
- 1977-06-06 CA CA279,922A patent/CA1095921A/en not_active Expired
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- 1977-06-22 PT PT66694A patent/PT66694B/en unknown
- 1977-06-22 AT AT0440477A patent/AT362790B/en not_active IP Right Cessation
- 1977-06-23 IT IT49950/77A patent/IT1106258B/en active
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- 1977-07-21 GB GB4243/78A patent/GB1538375A/en not_active Expired
- 1977-07-21 PL PL1977199798A patent/PL115586B1/en unknown
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- 1977-07-21 SU SU772508256A patent/SU955859A3/en active
- 1977-07-21 GB GB4242/78A patent/GB1538374A/en not_active Expired
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- 1977-07-21 HU HU77PI584A patent/HU180040B/en unknown
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1978
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- 1978-05-25 JP JP6282278A patent/JPS5436271A/en active Granted
- 1978-05-25 JP JP6282178A patent/JPS5436270A/en active Granted
- 1978-05-25 JP JP6281978A patent/JPS5436268A/en active Pending
- 1978-05-25 JP JP53062820A patent/JPS5814433B2/en not_active Expired
- 1978-05-25 JP JP6281778A patent/JPS5436266A/en active Pending
- 1978-05-25 JP JP6281878A patent/JPS5436267A/en active Granted
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- 1978-06-07 CS CS783705A patent/CS203922B2/en unknown
- 1978-06-13 ES ES470745A patent/ES470745A1/en not_active Expired
- 1978-06-13 ES ES470743A patent/ES470743A1/en not_active Expired
- 1978-06-13 ES ES470746A patent/ES470746A1/en not_active Expired
- 1978-06-13 ES ES470744A patent/ES470744A1/en not_active Expired
- 1978-07-05 SU SU782631651A patent/SU1015826A3/en active
-
1979
- 1979-02-01 PH PH22150A patent/PH13874A/en unknown
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-
1980
- 1980-03-06 AT AT0124380A patent/AT364356B/en not_active IP Right Cessation
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1981
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1982
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1983
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1986
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