SE445042B - PROCEDURE FOR MANUFACTURING GAMMA PYRONS - Google Patents

Description

No. 8200519-0 2 according to the method described in U.S. Pat. No. 3,468,915.

Syntheses of gamma-pyrones such as pyromeconic acid, maltol, ethyl-maltol and other 2-substituted 3-hydroxy-gamma-pyrones are described in U.S. Pat. Nos. 3,130,204; 3,133,089; 3,140,239; 3,159,652; 3,365,469; 3,376,317; 3,468,915; 3,440,183 and 3,446,629.

Maltol and ethyl maltol enhance the aroma and taste of a variety of food products. In addition, these compounds were used as components in perfumes and essences. The 2-alkenyl pyromeconic acids are reported in U.S. Pat. No. 3,644,635 and the 2-arylmethylpyromeconic acids are described in U.S. Pat. No. 3,365,469, which inhibit the growth of bacteria and fungi and are useful as flavorings in foods and beverages. and as odor-enhancing agents in perfumes.

Patent 433 079 discloses a process for the preparation of a 3-hydroxy-4-pyrone derivative by acid hydrolysis of a 3-pyrone derivative, which is characterized in that a gamma-pyrone having the formula II (I) in R wherein R represents hydrogen or alkyl of 1-4 carbon atoms and R "'represents hydrogen or alkyl of 1-4 carbon atoms, starting from a 4-halo-dihydropyran having the formula (II) or a 6,6' oxibis [4-halo-2H-pyran-3 (6H) -one] of the formula (V): XXX Pill _ or \ \\\ _ or Q / íi '' V) (II) (8200519-0 wherein R "'has the meaning given above and R' represents hydrogen, alkyl of 1-4 carbon atoms or -COR", wherein R "is methyl, ethyl or phenyl and X represents chlorine or bromine.

The acid required for the hydrolysis can be added to the reaction mixture, e.g. by dissolving the intermediate compound of formula (II) or formula (V) in an aqueous solution of inorganic or organic acid before heating; or alternatively the acid may be formed in situ during the preparation of the intermediate as described below.

The intermediate compound of formula (II) above can be prepared by reacting a compound having the formula / R ... (IV) Rno / \ OR wherein R, R 'and R "' have the meaning given above, in a solution means at a temperature of -50 ° C to SOOC, preferably at room temperature, with at least one molar equivalent of a halogen-containing oxidant selected from chlorine, bromine, bromine chloride, hypochlorous acid, hypobromic acid or mixtures thereof, until the reaction is substantially complete.

Examples of suitable solvents for this reaction are water, an alkanol or diol having 1-4 carbon atoms, preferably methanol, an ether having 2-10 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 may be prepared by reacting a furfuryl alcohol having the formula 8200 wherein R and R 7 "are as defined above, in aqueous solution having at least one equivalent of a halogen-containing oxidant selected from chlorine, bromine, bromine chloride, hypochlorous acid, hypobromic acid or mixtures thereof, at a temperature of -50 ° C to SOOC, preferably at room temperature, until the reaction is Substantially complete. of a co-solvent, which may suitably be one of the abovementioned solvents for the preparation of the intermediate compound of formula (II).

If desired, the intermediate 4-halo-dihydropyran compound of formula (II) may be prepared directly from a suitable furfuryl alcohol of formula (III) by reacting the latter in a solvent at a temperature of -50 to 50 ° C with at least two equivalents of one of the abovementioned halogen-containing oxidants until the reaction is substantially complete.

In each of the reactions described above, the preferred halogen-containing oxidants are chlorine or bromine chloride.

The gamma-pyrones of formula (I) may also be prepared directly from the intermediates of formula (IV) and, consequently, the present invention relates to a process for the preparation of a gamma-pyrone having the formula 0 H OH a wherein R is hydrogen or alkyl of 1-4 carbon atoms, and R "'represents hydrogen or alkyl of 1-4 carbon atoms, which is characterized in that a compound having the formula 8200519-0 5 á _ // O RI 1 I Wherein R and R "'are as defined above and R' represents hydrogen, alkyl having 1-4 carbon atoms or -COR", wherein R "is methyl, ethyl or phenyl, is reacted in acidic aqueous solution with at least one equivalent of a halogen-containing oxidant selected from chlorine, bromine, bromine chloride, hypochlorous acid, hypobromic acid or mixtures thereof and the reaction mixture is heated until hydrolysis of the intermediate is substantially complete.

According to a preferred embodiment of the invention, the intermediate compound of formula (IV) is 6-methoxy-2-methyl-2H--pyran-3 (6H) -one, the solution is aqueous acetic acid and the oxidant is gaseous chlorine and the product obtained is 2-methyl-3-hydroxy-4H-pyran-4-one.

A 6-alkoxy-2H-pyran-3 (6H) -one can be prepared according to the method described in Tetrahedron Letters no. 17, 1363-1364 (1976).

A furphyryl alcohol is anoxylated anodically to 2- (1-hydroxyalkyl) -2,5-dialkoxy-dihydrofuran. Treatment with a strong organic acid gives the desired 6-alkoxy compound. A 6-acyl compound can be prepared by conventional treatment of the 6-hydroxy compound with the appropriate anhydride in the presence of pyridine.

A 6-acyl or 6-alkoxy-2H-pyran-3 (6H) -one is dissolved in a solvent selected from acetic acid, formic acid, trifluoroacetic acid, halogenated solvents, ethers, C1-C4 alkanols or diols, or low molecular weight ketones, nitriles, esters or amides.

The preferred solvent is acetic acid, formic acid or methanol. An equivalent of a halogen-containing oxidant selected from chlorine, bromine, bromine chloride, hypochlorous acid, hypobromic acid or mixtures thereof, is added at room temperature and the reaction mixture is heated to 70-160 ° C, usually to 100-110 ° C, until the conversion to the desired gamma-pyrone is essentially complete (approximately 1-3 hours). Gamma-pyrone 8200519-0 r. - ._.._. Can be obtained from the cooled, neutralized reaction mixture upon storage or by extraction of the reaction mixture with a solvent such as chloroform, which gives the gamma-pyrone after concentration.

With organic acids and other protic solvents such as formic acid, acetic acid, other organic acids and alkanols which have not been heavily dried, no additional water is added in the above-described reaction. However, when non-protic solvents are used, water is necessary and is added to convert the intermediate 4-halo-6-substituted-2H-pyran-3 (6H) -one formed in situ to the pyrone. When a low-boiling solvent is used in the reaction, it is removed by distillation immediately before the reaction mixture is heated to 100-10 ° C for the hydrolytic conversion of the intermediate 4-halo-dihydropyran to the gamma-pyrone. The 4-halo-dihydropyran of formula (II), which is formed in situ during the above reaction, is readily hydrolyzed to the gamma-pyrone by heating for about 1 hour in aqueous solution, optionally adding acid, preferably at a temperature in the range of 70- 160 ° C, more preferably 100-110 ° C.

This process, wherein the 6-acyl or 6-alkoxy-2H-pyran-3 (6H) -one is reacted in an organic solvent with one equivalent of a halogen-containing oxidant and the in situ formed intermediate 4-halo-dihydropyrane is heated until conversion to the desired gamma-pyrone is substantially complete differs from the multi-step procedure described by Shono and Matsumura in Tetrahedron Letters II, 1363 (1976), wherein the 6-alkoxy-2H-pyran-3 (GH) -one is treated with a metal solution of hydrogen peroxide with sodium hydroxide solution to form an epoxy tone. The isolated epoxy tone is then refluxed in water with Dowex 50 ion exchange resin to form the desired gamma pyrone.

The following examples illustrate the preparation of the gamma-pyrone according to the process of the invention. Example 1 illustrates the preparation of the intermediates of formula (IV).

In the examples in which spectral data occur, NMR chemical data are given by means of symbols which are conventional in the literature and all changes are expressed as 5-units from tetramethylsilane: s = singlet d = doublet t = triplet q = quartet m = multiplet br = broad Example gel of starting compounds (a) 6-hydroxy-2-methyl-2H-pyran-3 (GH) -one To a solution of 25 g of 1- (2-furyl) -1-ethanol in 125 ml of tetrahydrofuran and 125 ml of water at 5 ° C was added 1 equivalent of bromine.

The temperature was maintained at 5-10 ° C during the addition. The solution was adjusted to pH 2.1 and extracted with ethyl acetate (3 x 50 ml). The ethyl acetate extract was dried and evaporated to give a yellow oil. The oil was chromatographed on silica gel eluting with chloroform / ethyl acetate (3: 1) to give 4.8 g of a clear oil, which by spectral data was found to be identical with 6-hydroxy-2-methyl-2H-pyran -3 (6H) -one prepared from 6-methoxy-2-methyl-2H-pyran-3 (6H) -one by acid hydrolysis [Tetrahedron 21, 1973 (1997)].

: R-aata (cnc13> 3700, 33oo, 17000 cm -1 NMR (CDCl 3, δ): 6.8 ~ 7.1 (1H, d of d); 6.0-6.2 (1H, d), δ .6 (1H, br. S, yields with D 2 O); 5.4-5.5 (1H, d); 4.8-5.0 (1H, q); 1.3-1.6 (3H, The above procedure was repeated with a furfuryl alcohol having the formula: to give a compound having the formula o / 4 wherein R is hydrogen or ethyl .

Ethyl compound; IR (cnc13) azlo, 3340, 1706 cnfl compound: IR (cHc13) 3565, 3300, 1703 cm * Example 2 A solution of 6-methoxy-2-methyl-2H-pyran-3 (6H) -one (0.0l mol) in 20 ml of acetic acid was treated with gaseous chlorine (0.0l mol) at room temperature. The reaction mixture was then heated to reflux for about one hour, cooled to room temperature, diluted with 20 ml of water, the pH was adjusted with 50% NaOH solution pp 7.0 and the reaction mixture was extracted with chloroform. The chloroform extract was concentrated to give maltol, which was recrystallized from methanol to give the pure product (56%), m.p. 155.5-160.5 ° C.

Example Gel 3 The experiment of Example 2 was repeated starting from a compound having the formula wherein R is hydrogen, alkyl of 2-4 carbon atoms, phenyl or benzyl; R 'represents alkyl of 2-4 carbon atoms or -COR ". Wherein R" is methyl, ethyl or phenyl, to give a gamma-pyrone having the formula 0 wherein R is hydrogen, alkyl of 2-4 carbon atoms, phenyl or benzyl.

Example 4 The procedure of Example 2 was repeated with comparable results substituting acetic acid with each of the following solvents formic acid, methanol, ethanol, tetrahydrofuran, benzene, ethylene glycol, trifluoroacetic acid, acetone and acetonitrile.

Example 5 The experiment of Example 2 was repeated with comparable results, replacing chlorine with bromine, sodium or potassium hypochlorite or hypobromite, gaseous bromine chloride or bromine chloride prepared in situ by adding chlorine to a solution containing sodium bromide or bromine to a solution of sodium chloride.

Claims (3)

8200519-Û 10 PATENTKRAV A process for the preparation of a gamma-pyrone having the formula O OH I \ (I) 0 RIII R wherein R is hydrogen or alkyl of 1-4 carbon atoms and R "'represents hydrogen or alkyl of 1-4 carbon atoms , characterized in that a compound having the formula // / D (IV) P111 R'0 O wherein R and R "'have the meaning given above and R' is hydrogen, alkyl having 1-4 carbon atoms or -COR ", wherein R" is methyl, ethyl or phenyl, is reacted in acidic aqueous solution with at least one equivalent of a halogen-containing oxidant selected from chlorine, bromine, bromine chloride, hypochlorous acid, hypobromic acid or a mixture thereof and heating the reaction mixture until hydrolysis of the obtained The 4-halo-dihydropyran intermediate 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 70-16 ° C. 3. A process according to claim 1 or 2, characterized in that the intermediate compound of formula (IV) is 6-methoxy-2-methyl-2H-pyran-3 (6H) -one, the solvent is aqueous acetic acid, the oxidant is gaseous chlorine, and the product obtained is 2-methyl-3-hydroxy-4H-pyran-4-one.