SE445041B - PROCEDURE FOR MANUFACTURING GAMMA PYRONS - Google Patents

Description

820051852 Maltol and ethylmaltol enhance the aroma in a variety of different food products. These compounds are also used as components in perfumes and essences. 2-Alkenylpyromeconic acids are reported in U.S. Pat. No. 3,644,635 and 2-arylmethylpyromeconic acid is described in U.S. Pat. No. 3,365,469 as an inhibitory growth of bacteria and fungi and are useful as flavorings and flavor enhancers in foods and beverages and flavor enhancers.

The present invention relates to a process for the preparation of a gamma-pyrone having the formula / lon | | wherein R is hydrogen or alkyl of 1-4 carbon atoms and R "'is hydrogen or alkyl of 1-4 carbon atoms, which process is characterized in that it comprises reacting a compound having the formula _______ R 1 wherein R and R "'are as defined above, in aqueous solution 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, hypobromic acid or mixtures thereof and heating the resulting 4-halo-dihydropyran intermediate until the hydrolysis is substantially complete.

According to the invention there is thus provided a novel and easy synthesis of gamma-pyrones of the formula (II above, especially maltol (2-methyl-3-hydroxy-4H-pyran-4-one) and related compounds in a single vessel performed for In a single process carried out in a single process, a furfuryl alcohol in an aqueous medium is reacted with two equivalents of a halogenated oxidant and the reaction mixture is then heated for heating. The process carried out in a single vessel can be represented by the following equation: (III) wherein R is hydrogen or alkyl of 1-4 carbon atoms, R "'is hydrogen or alkyl of 1-4 carbon atoms; and XY is C12, Brz , C1Br, HOXI, HOBr or mixtures thereof The full reaction path is shown in the following scheme: X RI as ° ~ 0 '\ on (1111) vu____ _ e “' ëz fifi säëš fi ig ån sa- fi š fi 11 '<#____ __ QUNJTY' X o 3 t _ // 49 _ -f I /, on d Ü * lf-t í l Ukvn / 'XÜ \ R_' Ran \\ OR 'oH __ T1 (11') öppenked jig taui-: omer Poon ._______ 8200518-2 Lefebvre et al. showed in J. Med, Chem., Ig, 1084 (1973) 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 was used. . The first step according to Lefebvre utilizes a peracid in an organic solvent and probably leads to a 6-acetoxy or 6-m-chlorobenzoyloxypyrane derivative, which is hydrolyzed to the 6-hydroxy compound during the work-up in the presence of water. Water was not used in the first step of the reaction and would in fact be harmful. In any case, the process according to Lefebvre et al cannot directly lead to the conversion of a furfuryl alcohol into a gamma-pyrone.

Critical to the process for preparing the intermediates of the invention is the use of an aqueous solution of a halogen-containing oxidant. A furfuryl alcohol can be purely oxidized to a 6-hydroxy-2H-pyran-3 (6H) -one using an equivalent of a halogenated oxidant in water or water / organic cosolvent. It is surprising and unexpected to find that 6-hydroxy-2H-pyran-3 (6H) -ones can be converted to gamma-pyrones. A 6-hydroxy-ZH-pyran-3 (6H) -one can be considered as a hemiacetal of an aldehyde and as such it can be expected to undergo a number of undesirable side reactions such as over-oxidation or aldol-type condensations. Using two equivalents of a halogen-containing oxidant in water or water and an organic co-solvent, the reaction proceeds readily from a furfuryl alcohol to a gamma-pyrone. This new process performed in a single vessel offers the advantages of using inexpensive C12, Brz, BrCl, HOCl, HOBr or mixtures thereof as the halogen-containing oxidizing agent.

Isolation of the desired gamma-pyrone is greatly simplified because solvent, oxidant and mineral acid by-product are all volatile and can be removed in vacuo to obtain crude gamma-pyrone directly in high yield by simple concentration.

The process carried out in a single vessel was carried out by dissolving a furfuryl alcohol in water or water and a co-solvent. The cosolvent may be miscible or immiscible with water and may be selected from a wide range of solvents such as C 1 -C 4 alkanols or diols, for example methanol; G2-C10 ethers, for example tetrahydrofuran or isopropyl ether; low molecular weight ketones, for example acetone; low molecular weight nitriles are low molecular weight esters and low molecular weight amides. The preferred co-solvents in QUALITY 8200518-2 are C 1 -C 4 alkanols and C 2 -C 10 ethers, with methanol being preferred because of the cost. The solution is maintained at a temperature of -50 to 50 ° C, preferably from -10 to 10 ° C. To this solution is added a desired furfuryl alcohol while simultaneously reacting the reaction mixture with a halogen-containing oxidant (two equivalents). The temperature of the reaction mixture is poured at -50 DEG to 50 DEG C., preferably -10 DEG to 10 DEG C., below the reaction rate.

If a low-boiling co-solvent is used, this is removed by distillation after complete additions. The reaction mixture is then heated to a temperature at which the hydrolysis proceeds at an acceptable rate, for example 70-160 ° C. The commonly used hydrolysis temperature is 100-110 ° C. Heating is continued until the hydrolysis of the 4-halo-dihydropyran intermediate formed is substantially complete (usually 1-2 hours). The acid necessary for the catalysis of this final hydrolysis is formed 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-containing oxidant is selected from chlorine, bromine, bromine chloride, hypochlorous acid or hypobromic acid or mixtures thereof.

Bromine chloride is a commercially available gas. It can be prepared in situ by adding chlorine to a solution of sodium or potassium bromide or by adding bromine to a solution of sodium or potassium chloride. Hypochlorous acid and hypobromic acid may conveniently be formed in situ by the addition of aqueous acid (HCl, H 2 SO 4 or HBr) to a solution of an alkali metal or alkaline earth metal hypohalite, e.g. NaOCl, KOCl or Ca (OCl) 2. Based on cost factors, the preferred halogen-containing oxidants chlorine and bromine chloride are produced in situ.

The following examples illustrate the preparation of the gamma-pyrones using the process of the invention.

In the examples where spectral data are given, NMR chemical data are reported with symbols according to conventional literature and all changes are expressed as § units from tetramethylsilane: 8200518-2 [i 6 s = singlet t = triplet q = quartet Example 1 In a three-necked round-bottomed flask, equipped with a magnetic stirrer, a gas inlet tube, a thermometer and an additional dropping funnel, 20 ml of tetrahydrofuran and 50 ml of water were introduced. The solution was cooled to a temperature of 0-10 ° C. The additional dropping funnel was charged with a solution of 1- (2-furyl) -1-ethanol (0.089 mol) in 20 ml of tetrahydrofuran and this material was introduced dropwise into the stirred reaction flask while chlorine (0.30 mol) 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 (about 30 minutes) while maintaining the temperature below 10 ° C. The reaction mixture was heated to reflux and the tetrahydrofuran was removed by distillation. When the reaction mixture reached a temperature of about 105 ° C, a condenser was added and refluxing was continued for about 2 hours. The reaction mixture was then filtered hot, cooled, the pH was adjusted to 2.2 and the reaction mixture was cooled to 5 ° C. Crystallization and filtration gave 3.43 g of crude 3-hydroxy-2-methyl-72 pyrone (maltol). The aqueous filtrate was extracted with chloroform to give 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. 155.5-160.5 ° C.

Example 2 The procedure of Example 1 was repeated under varying conditions as shown in Table I below with furfuryl alcohols of the formula: oxidant R - Co-solvent Temp. (° C) 0200518-2 'Table II a vessel performed using chlorine as Yield as (Yield) CH3 methanol CH3 methanol CH3 methanol CH3 methanol CH3e methanol CH3 THF CH3 acetone CH3 CH3CN CH3 EtOAc CH3 no CH3 benzene CH3 methylisobutyl ketone CH3Zopropylalko methanol CHZCH3 methanol CHZCH3 THF H methanol CH3 methanol THF = tetrahydrofuran EtOAc = ethyl acetate Example 3 Temp. (° C) upon oxidation at hydrolxs -10 l0 5 ll0 -5 l04 -10 104 -20 l06 l0 l05 -5 ll0 -5 ll0 0 ll0 10 ll0 l0 110 5 ll0 0 ll0 5 ll0 -10 ll0 10 ll0 -l0 ll0 - 30 ll0 45 56 60 77 62-67 49 36 29 26 17-30 26 44 49 49 58 47 57 50 The procedure of Example 2 was repeated with comparable results using each of the following cosolvents: ethanol, n-propanol, isobutanol , n-butanol, t-butanol, dioxane, ethyl ether, 2-ethoxyethanol and ethylene isopropyl ether, dimethoxyethane, 2-methoxyethanol, glycol. Éšš flfl ålli 20 ml of tetrahydrofuran, 50 ml of water and sodium bromide (0.20 mol) were introduced into a three-necked, round-bottomed flask equipped with a stirrer, a gas inlet tube and a supply funnel. The solution was cooled to a temperature of 0-20 ° C. The addition funnel was charged with a solution of 1- (2-furyl) -1-ethanol (0.1 mol) in 20 ml of tetrahydrofuran and this was added dropwise to the rapidly stirred reaction flask while adding gaseous chlorine (0.40 mol) via the gas inlet tube. The alcohol was added at such a rate that a yellow-orange color was maintained. The temperature was kept below 20 ° C with ice bath cooling. When both the alcohol and the chlorine were added to the reaction flask, the temperature was increased to reflux to distill off tetrahydrofuran. The isolation procedure of Example 1 was applied to isolate 12.47 g of pure maltol (55% yield). Substantially the same result was obtained using potassium bromide instead of sodium bromide.

Example 5 The procedure of Example 4 was repeated under varying conditions, as shown in Table II below, with furfuryl alcohols of the formula: Table II- In a vessel performed procedure using BrCl as oxidant, formed in situ by the addition of chlorine to Naßr R Co-solvent . (QC) Temp. (OC) Oxidation yield on hydrolysis (%) CH3 THF _ 20 l04 55 CH3 THF 27 ll0 54 CH3 THF _ 15 íll0, 52 CH3_ isopropyl ether 25 ll0 46 CH3 ethyl ether 20 ll0 43 CH3 acetone 15 l05 47 CH3 CH30H l5 ll0 32 CHZCH3 THF 16 116 134 H THF 20 109 48 THF = tetrahydrofuran 8200518-2 'Example 6 In a three-necked round bottom flask equipped with a magnetic stirrer, a gas inlet tube, a thermometer and an addition funnel, 50 ml of tetrahydrofuran and 50 ml of water were introduced. . This solution was then cooled to 0 ° C and chlorine (1.0 mol) was slowly added to the reaction flask while adding 1 (2-furyl) -1-ethanol (0.09 mol) dropwise. The temperature of the reaction mixture was not allowed to exceed 10 ° C. Bromine (1.0 mol) was then added and the reaction mixture was heated to reflux. After isolation according to Example 1, a yield of 5.7 g of maltol was obtained. Example 7 In a four-necked round bottom flask equipped with a thermometer, cooler and two addition funnels, 50 ml of tetrahydrofuran and 50 ml of water were introduced and the solution was cooled to 10 ° C. To this well stirred solution was added together in the two addition funnels bromine (0.20 mol) and 1 (2-furyl) -1-ethanol (0.09 mol). The temperature of the mixture was maintained at 155 DEG C. during the double addition. The reaction mixture was then heated to 75 ° C for 10 hours. Maltol was isolated according to the procedure of Example 1 (53% yield).

Example 8 The experiment of Example 7 was repeated under varying conditions, as shown in Table III, with furfuryl alcohols according to the formula: [α] (OU Table III R samiosningseaei Temp. (° .c) Temp. (° c) yield on oxidation by hydrolysis ( %) cH3 THF i Ts * 75 53 cH3 cH3oH s Tos 47 CH3 no l5 100 30 cH2cH3 THF 25 Tos 47 H THF Ts Too 45 CH3 THF 50 100 20 8200518-2 _; _ .. ...,. '_; 4Example 9.

A 2.8M sodium hypochlorite solution was prepared by introducing 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 mol) in 15 ml of tetrahydrofuran and 15 ml of water was prepared in a three-necked flask and cooled to 5 ° C. While maintaining a pH of 1.0 to 0.8 with 6N HCl, 21.7 ml of hypochlorite solution was added dropwise to the reaction flask over a period of about 33 minutes while maintaining the temperature below 5 ° C, 15 ml of concentrated hydrochloric acid was then added to the reaction mixture. which was then heated to remove tetrahydrofuran by distillation. Heating was continued for another hour. Maltol was isolated as described in Example 1. Substantially the same result was obtained when sodium hypobromite was used instead of sodium hypochlorite.

Example 10 To a solution of 1- (2-furyl) -1-ethanol (0.05 mol) in 15 ml of tetrahydrofuran and 15 ml of water at 5 ° C was added 21.7 ml of 2.8M sodium hypochlorite solution. Chlorine (0.05 mol) was introduced into the reaction flask via a gas inlet tube while maintaining the temperature below 506. The reaction mixture was then heated to reflux and the tetrahydrofuran was removed by distillation. Heating was continued for another hour. The reaction mixture was cooled and maltol was isolated according to the procedure of Example 1.

Example 11 A three-necked round bottom flask was charged with a solution of 50 ml of water and 20 ml of tetrahydrofuran and the solution was cooled to 0 ° C. A addition funnel was charged with a solution of 1- (2-furyl) -1-ethanol (0.89 mol) in 25 ml of tetrahydrofuran and this solution was added dropwise to the reaction flask while adding BrCl (0.30 mol) via a gas inlet pipe.

The rate of addition was such that all of the furfuryl alcohol was added in the first 1.3-1.5 equivalents of BrCl while maintaining the temperature below 30 ° C. The reaction mixture was heated to reflux and the tetgahydrofuran was removed by distillation. When the temperature reached 105 ° C, a condenser was turned on and the reaction mixture was heated under reflux for about 2 hours. The reaction mixture was cooled and maltol was isolated according to Example 1. 8200518-2 11 "Example 12 A three-necked round bottom flask, equipped with a magnetic stirrer, thermometer and two addition funnels, was charged with 25 ml of tetrahydrofuran and 50 ml of water. To this solution was added 1 (2 -furyl) -1-ethanol (0.89 mol) in 25 ml of tetrahydrofuran while bromine (0.6 mol) was added dropwise while maintaining a temperature below 15 ° C. After complete additions, chlorine (0.10 mol) was added. ) via a gas inlet tube and the reaction mixture was heated to reflux Maltol was isolated from the cooled solution of Example 1.

Example 13 6-Methyl-2-ethyl-3-hydroxy-4H-pyran-4-one 28 ml of methanol and 38 ml of water were introduced into a three-necked round bottom flask.

The solution was cooled to -15 ° C and 0.166 moles of 5-methyl-2- (2-hydroxypropyl) -furan (J. Org. Chem., 26, 1673, 1960) and 0.416 moles of chlorine were added simultaneously. During the addition, the temperature was kept between -16 and -800.

When the addition was complete, the solution was heated to 8000 and refluxed for about 3 hours. After cooling to room temperature, the pH was adjusted to 2.1 and the mixture was 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, evaporated to give a thick dark solid. The solid was recrystallized twice from methanol to give 8.06 g (30% yield) of white solid. Sublimation gave a pure product, melting point 1s7-1s9 ° c.

Analysis: Calculated for C 8 H 100 O 3: C 62.33 H 6.54 Found: C 62.05 H 6.44 NMR (CdCl 3, δ): 6-CH 3, 2.33 (3H, S); 2-CH 3, 1.30 (3H, t); 2-CH 2, 2.75 (ZH, quartet), 5H, 6.23 (1H, s).

Example 14 2,6-Dimethyl-3-hydroxy-4H-pyran-4-one In a three-necked round bottom flask, 28 ml of water and 32 ml of methanol were introduced and the mixture was cooled to -15 ° C. The solution was treated with 0.167 moles of 5-methyl-2- (aehydroxyethyl) furan (J. Org. Chem., 26, 1673 (1960) and 0.416 moles of chlorine simultaneously. The temperature was maintained at -15 ° to -1000 during the addition). The mixture was allowed to warm to room temperature for 30 minutes and heated to reflux for 3 hours. The cooled solution was adjusted to pH 2.1 and extracted with chloroform (3 x 100 ml). The chloroform extracts were combined, washed with water and brine, dried over ammonium sulfate, filtered and evaporated. The residue, a dark oil, was chromatographed on silica gel which was quenched with methylene chloride / ethyl acetate (95: 5).

The product, which was isolated by evaporation, was recrystallized from methanoi as a tan solid (yield 25%). Subimulation gave white crystals, mp 161-1es ° C. 1 a Ana1ys:.

Calculated for C 7 H 80 2: C 59.99 H 5.75 Found: C 59.83 H 5.82 NMR (CDCl 3, 2); 6-CH 3, 2.33 (3H, s); 2-CH 3, 2.26 (3H, s); 5-H, 6.10 (1H, s). fifi ooí * ouAuTv

Claims (4)

8200518-2 "I _ 13 PATENT REQUIREMENTS 1. A process for the preparation of a gamma-pyrone having the formula 0 H \ on g _ | u) 0 n RIII wherein R is hydrogen or alkyl of 1-4 carbon atoms and R "'is hydrogen or alkyl of 1-4 carbon atoms, characterized in that a compound having the formula Oll / \ ... (III) R 11, wherein R and R "'have the meaning given above, to react in aqueous solution at a temperature of -50 to 5006 with at least two equivalents of a halogen-containing oxidant selected from chlorine, bromine, bromine chloride, hypochlorous acidity , hypobromic acid or mixtures thereof and heating the 4-halo-dihydropyran intermediate formed until the hydrolysis is substantially complete. 2. A process according to claim 1, characterized in that the temperature at which the hydrolysis is carried out is in the range of 70: 160%. , 3. A process according to claim 1 or 2, characterized in that the reaction is carried out in the presence of a co-solvent consisting of an alkanol or a diol having 1 to 4 carbon atoms, an ether having 2 to 10 carbon atoms, a low molecular weight ketone, nitrile , ester or amide. 8200518-2 14 4. A process according to claim 3, characterized in that the co-solvent is methanol, tetrahydrofuran, isopropyl ether or acetone. 5. A process according to any one of claims 1-4, characterized in that the halogenated oxidant is chlorine or bromine chloride.