IE45641B1

IE45641B1 - Process for the preparation of gamma-pyrones

Info

Publication number: IE45641B1
Application number: IE1587/77A
Authority: IE
Original assignee: Pfizer
Priority date: 1976-08-02
Filing date: 1977-07-29
Publication date: 1982-10-20
Also published as: FI831701L; IE45643B1; NL182805C; CH625798A5; NO150560B; DK325986D0; IE790584L; RO78953A; BE855965A; YU40166B; JPS5814433B2; BG28988A4; DK154079C; CS203922B2; ES470743A1; ATA124380A; PH15185A; LU77600A1; YU166383A; IE790585L

Abstract

The gamma-pyrones of formula I in which the symbols have the meaning given in Claim 1 are obtained by a simple and economic "one-pot" process by reaction of a furfuryl alcohol of formula III with at least 2 equivalents of a halogenated oxidising agent, in aqueous solution at a temperature of between -50 DEG and +50 DEG C, and then the reaction mixture is heated until hydrolysis of the intermediate formed is virtually complete. The gamma-pyrones obtained can be used as products which enhance flavour and fragrance in food and cosmetic preparations.

Description

This invention relates to a process for the preparation of gamma-pyrones and is particularly concerned with a process for the preparation of maltol (3-hydroxy-2-methyl4H-pyran-4-one) and related compounds.

Maltol is a naturally occurring substance found in the bark of young larch trees, pine needles and chicory. Early commercial production was from the destructive distillation of wood. Synthesis of maltol from 3-hydroxy-2-(1-piperidylmethyl) - γ - pyrone was reported by Spielman and Freifelder in J. Am. Chem. Soc., 69,2908 (1947). Schenck and Spielman, J. Am. Chem. Soc., 67, 2276 (1945), obtained maltol by alkaline hydrolysis of streptomycin salts. Chawla and McGonigal, J. Org. Chem., 39, 3281 (1974) and Lichtenthaler and Heidel, Angew. Chem., 81, 998 (1969), reported the synthesis of maltol from protected carbohydrate derivatives. Shono and Matsumura, Tetrahedron Letters No. 17, 1363 (1976), described a five step synthesis of maltol starting with methyl furfuryl alcohol.

The. isolation of 2-ethyl-3-hydroxy-6-methyl-4H-pyran20 4-one as one of the characteristic sweet-aroma components in refinery final molasses was reported by Hiroshi Ito in Agr. Biol. Chem., 40 (5), 827-832 (1976). This compound was previously synthesized by the process described in U.S. 3,468,915.

Syntheses of gamna-pyrones such as pyromeconic acid, - 3 4 5 6-11 rnalfcol, ethyl maltol and other 2-substituted-3-hydroxy~ gamma-pyrones are described in U.S. Patents 3,130,204; 3,133,089; 3,140,239; 3,159,652; 3,365,459; 3,376,317; 3,468,915; 3,440,183 and 3,446,629.

Maltol and ethyl maltol enhance the flavour and aroma of a variety of food products. In addition, these materials are used as ingredients in perfumes and essences. The 2alkenylpyromeconic acids reported in U.S. 3,644,635 and the 2-aryImethylpyromeconic acids described in U.S. 3,365,469 inhibit the growth of bacteri and fungi and are useful as flavour and aroma enhancers in foods and beverages an d aroma enhancers in perfumes.

Thus, according to the invention there is provided a process for preparing a gama-pyrone of the general formula: wherein R is hydrogen, alkyl of 1 to 4 carbon atoms, phenyl or benzyl; and R' is hydrogen or alkyl of 1 to 4 carbon atoms which comprises contacting a furfuryl alcohol of the general formula: R - 4 43042with at least two equivalents of a halogen oxidant at a temperature of -50 to +50°C. and without. isolating the 4halo-6-hydroxy-2,6-dihydropyran-3-one so formed, heating at 7O-16O°C until hydrolysis is substantially complete.

The process is generally performed by treating the furfuryl alcohol, in aqueous medium, with two equivalents of oxidant, although excess oxidant may be used, and the reaction mixture is then heated to hydrolyse the intermediate formed. The overall reaction is represented as follows: H2° XY 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 XY is Cl2, Br^, CIBr, H0C1, HOBr or mixtures thereof.

The reaction pathway is shown in the following scheme: ώ to ·Ζ A- opan chain tautomer opan chain tautomer 3 6 41 -6Lefebvre and co-workers in J. Med. Chem., 16, 1084 (1973) demonstrated that furfuryl alcohols could be directly converted to 6-hydroxy-2H-pyran-3(6H)-ones when a peracid oxidant such as peracetic acid or m-chloroperbenzoic acid is employed. The first step of the Lefebvre work uses a peracid in an organic solvent and probably leads to a 6acetoxy or 6-m-chlorobenzoyloxy pyran derivative which is hydrolyzed to the 6-hydroxy compound during the aqueous workup. Water is not used in the first step of the reaction, and would in fact be deleterious. In any case, the process of Lefebvre and co-workers cannot lead directly to the conversion of a furfuryl alcohol to a gamma-pyrone.

Critical to the process of the present invention is the use of an aqueous solution of a halogen oxidant. A furfuryl alcohol can be cleanly oxidized to a 6-hydroxy-2H-pyran-3(6H) one using one .equivalent of a halogen oxidant in water or water/organic co-solvent. it is surprising and an unexpected finding that: 6-hydroxy-2H-pyran-3(6H)-ones can be converted to gamma-pyrones. A 6-hydroxy-2H-pyran-3(6H)-one may be regarded as a hemi-acetal of an aldehyde and as such might be expected to undergo numerous undesired side reactions such as over oxidation, aldo1-type condensations, etc. Employing two or more equivalents of halogen oxidant in water or water and organic co-solvent, the reaction proceeds smoothly from a furfuryl alcohol to a gamma-pyrone. This novel one pot process offers the advantages of employing low cost Cl^, Br2> CIBr, H0C1, HOBr or mixtures thereof as the halogen oxidant. Isolation of the desired gamma-pyrone is greatly simplified since solvent, oxidant and by-product mineral acid are all volatile and can be removed in vacuo to afford crude garmia-pyrone directly in high yield by simple concentration.

The one-pot process is conveniently operated by dissolving a furfuryl alcohol in water or water and a co-solvent. The co-solvent can be water miscible or water immiscible and can be selected from a wide range of solvents such as to alkanols or diols; C„ to C^Q ethers or nitriles and C^-C^o ketones or esters. The preferred co-solvents are to alkanols and 2 to C ethers, with methanol the preferred solvent because of cost. The solution is kept at a temperature o o of -50 to 50 C, preferably -10 to 10 C. To this solution is charged a desired furfuryl alcohol while simultaneously adding a halogen oxidant (preferably two equivalents) to the reaction mixture. The temperature of the reaction mixture is maintained at -10 to 1O°C. during halogen addition. If a low-boiling co-solvent is employed, it is preferably removed by distillation after all additions are complete. The reaction mixture is then heated to a temperature at which the hydrolysis proceeds at a reasonable rate (70 to 160°C). The generally employed reaction temperature is 100-ll0°C. The heating is continued until the hydrolysis of the formed 4halo-6-hydroxy-2,6-dihydropyran-3-one intermediates is substantially complete (1 to 2 hours). The acid necessary to catalyse this final hydrolysis is generated in situ by loss of acid from the intermediates formed during the course of the reaction. Additional acid can be added if desired.

The halogen oxidant can be chlorine, bromine, chlorinebromide, hypochlorous or hypobromous acid or mixtures thereof. Chlorine-bromide is a commercially available gas. It can be prepared in situ by addition of chlorine to a solution of sodium or potassium bromide or by the addition of bromine to a solution of sodium or potassium chloride. 4o6 41 - 8 Hypochlorous and hypobromous acid can be conveniently generated in situ by the addition of aqueous acid (HCl, ^80^, HBr, etc.) to a solution of the alkali or alkali earth metal hypohalite, e.g. NaOCl, K0C1 or CafOCl)^. The preferred halogen oxidants, based on cost factors, are chlorine and chlorine-bromide prepared in situ.

The intermediates shown in the reaction scheme may also be isolated and reacted ijj. separate steps as described in Patent Specification. Nos. 45642 and 4^644 The process of the invention is-illustrated by the following Examples: Example 1 In a 3-neek round bottom flask equipped with a magnetic stirring bar, a gas inlet tube, a thermometer and an addition funnel was added 20 ml of tetrahydrofuran and 50 ml of water. The solution was cooled to a temperature of 0 to 10°C. The addition funnel was charged with a solution of 1(2-furyl)-1-ethanol (0.089 moles) in 20 ml of tetrahydrofuran and this was added dropwise to the stirred reaction flask while chlorine (0.30 mole) was added via the gas inlet tube. The rate of addition was such that all the alcohol was added in the first 1.3-1.5 equivalents of chlorine (approximately 30 minutes) while maintaining the reaction temperature below 10°C. The reaction mixture was heated to reflux and the tetrahydrofuran removed by distillation.

When the reaction mixture reached a temperature of about 105°C., a condenser 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 was cooled to 5°C. Crystallization and filtration yielded 3.43 grams of crude 3-hydroxy-2-methyl-Y pyrone (maltol). 6 4 £ - 9 The aqueous filtrate was extracted with CHC13 to obtain a second crop of 2.58 g of maltol. Distillation of the combined solids and recrystallization from methanol gave 5.5 g (49% ) of pure white maltol, m.p. 159.5-160.5°C.

Example 2 The method of Example 1 was repeated under varying conditions as shown in Table I with furfuryl alcohols of the formula R Table J . One Pot Process using chlorine as the oxidant.

R Cosolvent Temp.(°C) of oxidation Temp. (°C) of hydrolysis Yield {%) ch3 methanol 10 100 45CH3 methanol 5 110 56 ch3 methanol -5 104 60 ch3 methanol -10 104 77 ch3 methanol -20 105 . 62-67CH3 THF 10 105 49 -3 acetone -5 110 36 ch3 CH CH -5 110 29 ch3 Et OAc 0 110 26 CH none 10 110 17-30 «3 benzene 10 110 26 CH3 methyl isobutyl ketone 5 no 44 ch3 isopropyl alcohol 0 no 49 - ΙΟ Table 1 (Continued).

R Cosolvent Temp.(°C) of oxidation Temp. (°C) of hydrolysis Yield (%)CH2CH3 methanol 5 110 49CH2CH3 methanol -10 110 58CH2CH3 THF 10° 110 47 H methanol -10° 110 57 CH. methanol -30° 110 50 3 THF = tetrahydrofuran 10 ETOAc = ethyl acetate Example 3 The method of Example 2 was repeated with comparable results employing each of the following co-solvents: ethanol n-propanol iso-butanol n-butanol t-butanol dioxane ethyl ether isopropyl ether dimethoxy ethane . 2-methoxy ethanol 2-ethoxy ethanol ethylene glycol Example 4 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 of water and sodium bromide (0.20 mole). The solution was cooled to a temperature of & 5 ΰ -2 ί - 11 Ο to 20°C. The addition funnel was charged with a solution of 1(2-furyl)-1-ethanol (0.18 mole) in 20 ml of tetrahydrofuran and this was added dropwise fo the rapidly stirred reaction flask while gaseous chlorine (0.40 mole) is added via the gaseous inlet tube. The rate of the alcohol addition was such that a yellow orange color was maintained.

The reaction temperature was kept below 20°C. with ice bath cooling. After the alcohol and chlorine had both been added to the reaction flask, the temperature was raised to reflux to distill off the tetrahydrofuran. The isolation procedure of Example 1 was used to isolate 12.47 g of pure maltol (55% yield).

Substantially the same results are obtained substituting potassium bromide for sodium bromide.

Example 5 The mathod of Example 4 was repeated under varying conditions shown in Table 2 with furfuryl alcohols of the formula R 3 6 41 - 12 Table 2. One Pot Process using Cl-Br as the oxidant, generated by addition of chlorine in situ to NaBr.

R Cosolvent Temp. (°C) of oxidation Temp. (°C) of hydrolysis Yield (%> . 5 CH THF 20° 104 55 3 ch3 THF 27° 110 54 ch3 THF 15° 110 52 ch3 Isopropyl ether 25 110 46ch3 ethyl ether 20 110 43 10 CH acetone 15 105 47 ch3 CH30H 15 110 32 CH2ch3 THF 16 113 47 H THF 20 109 48 THP = tetrahydrofuran 15 Example 6 In a 3-neck round bottom flask equipped with a magnetic stirring bar, a gas inlet tube, a thermometer and an addition funnel was added 50 ml of tetrahydrofuran and 50 ml of water. This solution was then cooled to 0°C. and chlorine (0.10 mol§) was added slowly to the reaction flask while l(2-furyl1-ethanol (0.09 mole) was added dropwise. The temperature of the reaction mixture was not allowed to exceed 10°C. 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 maltol was obtained.

Example 7 To a 4-neck round bottom flask equipped with a thermometer, a condensor and two addition funnels was charged 50 ml of tetrahydrofuran and 50 ml of water and the solution was cooled to 1O°C. To this well stirred solution was added together in the two addition funnels bromine (0.20 mole) and 6 41 - 13 1(2-furyl)-1-ethanol (0.09 mole). The temperature of the o reaction was maintained at 15 C. throughout the double addition. The reaction mixture was then heated to 75°C. for 10 hours. Maltol was isolated by the procedure of Example 1 (53% yield).

Example 8 The method of Example 7 was repeated under varying conditions shown in Table 3 with furfuryl alcohols of the formula R Table 3 R Cosolvent Temp. (UC) of oxidation Temp. (°C) of hydrolysis Yield (%) CH THF 15° 75 53 % CH OH 5° 105 47 CH3 none 15° 100 30CH2CH3 THF 25 105 47 H THF 15° 100 45 CH_ THF 50° 100 20 3 Example 9 A 2.8 M sodium hypochlorite solution was prepared by passing chlorine gas (42.6 g) into a solution of 48 g of sodium hydroxide in 150 ml of water at 0°C. A solution of 1(2-furyl)-1-ethanol (0.05 mole) in 15 ml of tetrahydrofuran and 15 ml of v/ater was prepared in a 3-neck flask 3 6 41 - 14 and cooled to 5°C. While maintaining a pH from 1.0 to 0.8 with 6 N HCl, 21.7 ml of the hypochlorite solution was added dropwise to the reaction flask over a period of about 33 minutes while maintaining the reaction temperature below 5°C. A 15 ml portion of concentrated HCl was then added to the reaction mixture which was then heated to remove the tetrahydrofuran by distillation. Heating was continued for an additional hour. Maltol was Isolated as described in Example 1.

Substantially the same results are obtained when sodium hypobromite is used in place of sodium hypochlorite.

Example 10 To a solution of l(2-furyl)-l-ethanol (0.05 mole) in 15 ml of tetrahydrofuran and 15 ml of water at 5°C. is added 21.7 ml of 2.8 M sodium hypochlorite solution. Chlorine (0.05 mole) is added to the reaction flask via a gas inlet tube maintaining the reaction temperature below 5°C. The reaction mixture is then heated to reflux and the tetra hydrofuran removed by distillation. Heating is continued for an additional hour. The reaction mixture is cooled and maltol is isolated by the procedure described in Example 1.

Example 11 To a 3-neck round bottom flask is charged a solution of 50 ml of water and 20 ml of tetrahydrofuran and the solu· tion is cooled to 0°C. An addition funnel is charged with a solution of l(2-furyl)-l-ethanol (0.89 mole) in 25 ml of tetrahydrofuran and this solution is added dropwise to the reaction flask while BrCl- (0.30 mole) is added via a gas inlet tube. The rate of addition is such that all the furfuryl alcohol is added in the first 1.3-1.5 equivalents of BrCl while maintaining the temperature below 30°C. The 3 6 41 reaction mixture is heated to reflux and the tetrahydrofuran removed by distillation. When the temperature reaches 105°C., a condenser is attached and the reaction mixture heated under reflux for about 2 hours. The reaction mixture is cooled and maIto1 isolated by the method of Example 1.

Example 12 In a 3-neck round bottom flask equipped with a magnetic bar, a thermometer and two addition funnels is charged 25 ml of tetrahydrofuran and 50 ml of water. To this solution is added 1(2-furyl)-1-ethanol (0.89 mole) in 25 ml of tetrahydrofuran while bromine (0.16 mole) is added dropwise, maintaining the temperature below 15°C. After the additions are complete, chlorine (0.10 mole) is added via a gas inlet tube and the reaction mixture is heated to reflux. Maltol is isolated from the cooled solution by the method of Example I.

Example 13 2-Ethyl-3-hydroxy-6-methyl-4H-pyran-4-one In a three necked round bottom flask were combined 28 ml of methanol and 38 ml of water. The solution was cooled to -15°C. 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 addition, the reaction was maintained between -16 and -8°C. When addition was completed, the solution was warmed to 80°C. and refluxed for about 3 hours. Upon cooling to room temperature, the pH was adjusted to 2.1 and extracted with chloroform (3 x 100 ml). The combined organic layers were washed with water, brine and dried over magnesium sulfate.

The organic solution was filtered and evaporated to give a 3 6 41 - 16 thick dark solid. The solid was recrystallized twice from methanol to give 8.06 grams (30% yield) cfwhite solid. Sublimation yielded pure product, m.p. 157-159°C.

Ana lys is; Calc'd. for COH, 0 : C, 62.33? H, 6.54 o Xu 3 Found s C, 62.05; H, 6.44.

NMR (CDC13 δ ); 6-CH3, 2.33 (3H, s); 2-CH3, 1.30 (3H, t); 2- CH2~, 2.75 (2H, quartet); SH, 6.23 (IH, s).

Example 14 3- Hydroxy-2,6-dimethyl-4H-pyran-4-one In a three necked round bottom flask were combined 28 ml of water and 32 ml of methanol and cooled to -15°C. The solution was treated with 0.167 mole of 5-methyl-2-(ahydroxy-ethyl) furan (J. Org. Chem., 26., 1673, 1960) and 0.416 mole of chlorine simultaneously. The temperature was maintained at -15 to -10°C. during addition. The reaction was allowed to warm to room temperature over 30 minutes and heated to reflux for 3 hours. The cooled solution was adjus ted to pH 2.1 and extracted with chloroform (3 x 100 ml).

The chloroform extracts were combined, washed with water 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. 161-163°C.

Analysis : Calc'd for CHO: C, 59,99? H, 5.75 / o Found : 0,59.83? H, 5.82 NMR (CDCl3, δ)? 6-CH3, 2.33 (3H, s); 2-CH3< 2.26 (3H, s)? -H, 6.10 (IH, 's).

Claims

1. A process for preparing a gamma-pyrone of the general formula 5 which comprises contacting a furfuryl alcohol of the general formula wherein R is hydrogen, alkyl of 1 to 4 carbon atoms, phenyl or benzyl and R' is hydrogen or alkyl of 1 to 4 carbon 10 atoms in aqueous solution with at least two equivalents of a halogen oxidant selected from chlorine, bromine, chlorine-bromide, hypochlorous acid, hypobromous acid or mixtures thereof at a temperature of -50°C to +50°C and, without isolating the 4-halo-dihydropyran so formed heating 15 at 7O-16O°C, until hydrolysis is substantially complete.

2. The process of claim 1 wherein the hydrolytic reaction temperature is 100-ll0°c.

3. The process of claim 1 wheri in a co-solvent is present and said co-solvent is selected from alkanols or diols 20 of 1 to 4 carbon atoms, ethers or nitriles of 2 to 10 18 carbon atoms, and ketones or esters of 3 to 10 carbon atoms.

4. The process

5. The process hydrofuran. of claim 3 wherein of claim 3 wherein said alkanol is methanol said ether is tetra

6. The prooess propyl ether. of claim 3 wherein said ether is iso

7. The process

8. The process Is chlorine. of claim 3 wherein said ketone is acetone, of claim 1 wherein said halogen oxidant

9. The process of claim is chlorine-bromide. 1 wherein said halogen oxidant

10. The process of claim 1 wherein said gamma-pyrone is 3-hydroxy-2-methyl-4H-pyran-4-one.

11. The process of claim 1 wherein said gamma-pyrone is 2-sthyl-3-hydroxy-4H-pyran-4-one.

12. The process of claim 1 wherein said gamma-pyrone is 2-ethyl-3-hydroxy-6-methyl-4H-pyran-4-one.

13. A process as claimed in any one of claims 1 to 12 substantially as hereinbefore described with reference to any of the Examples.