NO150043B - PROCEDURE FOR MANUFACTURING GAMMA PYRONS - Google Patents

Description

Patent application 77.2193 concerns a process for the production of gamma-pyrones and in particular the production of gamma-pyrones by hydrolysis of certain intermediates, some of which are new, which intermediates are produced from suitable furfuryl alcohols using halogen-containing oxidizing agents. The present invention relates to a method for the production of gamma-pyrones from a 6-hydroxy-, 6-alkoxy- or 6-acyl-pyrone intermediate by oxidation and hydrolysis.

Maltol (2-methyl-3-hydroxy-4H-pyran-4-one) is a naturally occurring substance found in the bark of young larch trees, pine needles and chicory. Early commercial production took place by destructive distillation of wood. The synthesis of maltol from 3-hydroxy-2-(1-piperidylmethyl)-1,4-pyrone was discussed by Spielman and Freifelder in J. Am. Chem. Soc, 69, 2908 (1947). Schenck and J. Am. Chem. Soc, 67, 2267 (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), discussed the synthesis of maltol from protective carbohydrate derivatives. Shono and Matsumura, Tetrahedron Letters No. 17, 1363 (1976), described

a five-step synthesis of maltol starting from methylfurfuryl alcohol.

The isolation of 6-methyl-2-ethyl-3-hydroxy-4H-pyran-

4- on as one of the characteristic sweet-aroma constituents in refined, finished molasses was discussed by Hiroshi Ito in Agr.

Biol. Chem., 40 (5), 827-832 (1976). This compound was previously synthesized using the method described in US patent 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 US Patents 3,130,204, 3,133,089, 3,140,239, 3,159,652, 3,365,469, 3,376,317, 3,440,183 ,

3,446,629 and 3,468,915.

Maltol and ethyl maltol increase the taste and aroma of various foodstuffs. In addition, these compounds are used as ingredients in perfumes and essences. The 2-alkenylpyromeconic acids described in US patent 3,644,635 and the 2-arylmethylpyromeconic acids described in US patent 3,365,469 prevent the growth of bacteria and fungi and are useful as flavor and aroma enhancers in foodstuffs and beverages, and aroma enhancers in perfumes.

Patent application no. 77,2193 relates to a method for producing a 3-hydroxy-4-pyrone derivative by acid hydrolysis of a 3-pyrone derivative. A gamma-pyrone is prepared with the formula: where R is hydrogen or alkyl with 1-4 carbon atoms, and R"'' is hydrogen or alkyl with 1-4 carbon atoms, by starting with a 4-halo-dihydropyran of formula ( II) or a 6,6'-oxybis-[4-halo-2H-pyran-3(6H)-one] of formula (V):

where R and R''<1> are as above, R<1> is hydrogen, alkyl of 1 to 4 carbon atoms or -COR", where R" is methyl, ethyl or phenyl, and X is chlorine or bromine.

The acid required for the hydrolysis can be added

to the reaction mixture, e.g. by dissolving the intermediate of formula (II) or (V) in an aqueous, inorganic or organic acid prior to heating; or alternatively the acid can be generated in situ during the preparation of the intermediates as described later.

The intermediate product of formula (II) can be prepared by reacting a compound of the formula:

where R, R<1> and R<11>' are as defined above, in a solvent at a temperature of -50 to 50°C, preferably at room temperature, with at least one equivalent of a halogen-containing oxidizing agent 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 with 1 to 4 carbon atoms, preferably methanol, an ether with 2 to 10 carbon atoms, preferably tetrahydrofuran or isopropyl ether, a low molecular weight ketone, preferably acetone, a nitrile, a ester or a low molecular weight amide.

The intermediate with formula (IV) can be prepared by reacting a furfuryl alcohol with the formula:

where R and R" <1> are as defined above, in aqueous solution with at least one equivalent of a halogen-containing oxidizing agent selected from chlorine, bromine, bromine chloride, hypochloric acidification, hypobromic acidification or mixtures thereof at a temperature of -50 to 50°C, preferably room temperature, until the reaction is substantially complete.The reaction may be carried out in the presence of a co-solvent which may suitably be one of the solvents mentioned earlier in the preparation of the intermediate of formula (II).

If desired, the intermediate product 4-halo-dihydropyran

of formula (II) is 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 aforementioned halogen-containing oxidizing agents until the reaction is essentially complete.

In each of the reactions described above, the preferred halogen-containing oxidizing agent is chlorine or bromine chloride.

The gamma-pyrones of formula (I) can also be prepared directly from the intermediates of formula IV, and according to the present invention, a method for the preparation of a gamma-pyrone of the formula is provided: where R is hydrogen or alkyl with 1 to 4 carbon atoms, and R'<1>' is hydrogen or alkyl with 1 to 4 carbon atoms, and the method is characterized by the fact that a compound with the formula:

where R and R'<11> are as indicated above, and R<1> is hydrogen,

alkyl with 1 to 4 carbon atoms or -COR", where R" is methyl, ethyl or phenyl, is reacted in acidic, aqueous solution with at least one equivalent of a halogen-containing oxidizing agent selected from chlorine, bromine, bromine chloride, hypochloric acidification, hypobromic acidification or mixtures thereof, and the resulting 4-halo-dihydropyran intermediate is hydrolyzed by heating the reaction mixture.

In a preferred embodiment of the invention

is the intermediate of formula (IV) 6-methoxy-2-methyl-2H-pyran-3(6H)-one, the solution is an aqueous acetic acid solution, the oxidizing agent is gaseous chlorine, and the resulting product is 2r-methyl-3 -hydroxy-4H-pyran-4-one.

A 6-Alkoxy-2H-pyran-3(6H)-one can be prepared by the method described in Tetrahedron Letters No. 17, 1363-1364 (1976). A furfuryl alcohol is anodically alkoxylated to 2-(1-hydroxyalkyl)-2,5-dihydroxy-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)-qn dissolves

in a solvent selected from acetic acid, formic acid, trifluoroacetic acid, halogenated solvents, ethers, C 1 -C 4 alkanols or diols, or low molecular weight ketones, esters or amides. The preferred solvent is acetic acid, formic acid or methanol. One equivalent of a halogen-containing oxidizing agent selected from chlorine, bromine, bromine chloride, hypochloric acidification, hypobromic acidification or mixtures thereof is added at room temperature and the reaction mixture is heated to 70-160, usually 100-110°C, until the conversion to the desired gamma-pyrone is in essentially finished (approx. 1 to 3 hours). The gamma pyrone can be obtained from the cooled, neutralized reaction mixture by standing or by extracting the reaction mixture with a solvent such as e.g. chloroform, which gives gamma-pyrone on concentration.1

With organic acids and other protic solvents

like for example. formic acid, acetic acid, other organic acids and alkanols that have not been thoroughly dried, additional water is not added to the reaction described above. With non-protic solvents, however, water is necessary and is added to convert the intermediate 4-halo-6-substituted-2H-pyran-3(6H)-one,

which is formed in situ, to the pyronet. When a low-boiling solvent is used in the reaction, it is removed by distillation just before the reaction mixture is heated to 100 to 110°C for hydrolytic conversion of the intermediate 4-halo-dihydropyran to the gamma-pyrone.

The 4-halo-dihydropyran of formula II which is formed in situ by the above-mentioned reaction can be easily hydrolysed to the gamma-pyrone by heating for approx. 1 hour in aqueous solution, with added acid if desired, preferably at a temperature in the range 70 to 160, more preferably from 100 to 110°C.

This method in which the 6-acyl- or 6-alkoxy-2H-pyran-3(6H)-one is reacted in an organic solvent with an equivalent of a halogen-containing oxidizing agent and the intermediate product 4-halo-dihydropyran, which is formed in situ, is heated until the conversion to the desired gamma-pyraone is essentially complete differs from the multi-step process described

by Shono and Matsumura in Tetrahedron Letters 17, 1363 (1976)

where the 6-alkcksy-2H-pyran-3(6H)-one is treated with a methanol solution of hydrogen peroxide with sodium hydroxide solution to obtain an epoxy ketone. The isolated epoxy ketone is then refluxed in water with "Dowex" 50 ion exchange resin to give the desired gamma-pyrone.

The following examples illustrate the production of the gamma pyrones by the method according to the invention. Example 1 illustrates the preparation of the intermediate products of formula IV.

In the examples where spectral data are given, NMR chemical shift data are given using conventional literature symbolism and all shifts are expressed as 6-units from tetramethylsilane:

s = singlet

d = duplicate

t = triplet

q = quartet

m = multiplet

br= wide

Example 1

Production of starting materials

a) 6-hydroxy-2-methyl-2H-pyran-3(6H)-one

To a solution of 25 g of 1(2-furyl)-1-ethanol in 125 ml

tetrahydrofuran and 125 ml of water at 5°C was added 1 equivalent of bromine. The temperature was maintained at 5°C to 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 extracts were dried and evaporated to give a yellow oil. The oil was chromatographed on silica gel and eluted with chloroform-ethyl acetate (3:1) to give 4.8 g of a clear oil which was shown by spectral data to be identical to 6-hydroxy-2-methyl-2H-pyran-3( 6H)-one prepared from 6-methoxy-2-methyl-2H-pyran-3(6H)-one by acid hydrolysis (Tetrahedron 27,

1973 (1971).

IR (CHC13) 3700, 3300, 1700 cm"<1>.

NMR (CDCl 3 , 6): 6.8-7.1 (1H, d of d); 6.0-6.2 (1H, d), 5.6 (1H, br. s, exchanged with D 2 O); 5.4-5.5 (1H, d); 4.8-5.0 (1H, q); 1.3-1.6 (3H, t). b) The above procedure was repeated with a furfuryl alcohol of the formula: to give a compound with the formula:

where R is hydrogen or ethyl.

Ethyl compound: IR (CHC1,) 3600, 3340, 1706 cm-1 Hydrogen compound: IR (CHC13) 3565, 3300, 1703 cm .

Example 2

A solution of 6-methoxy-2-methyl-2H-pyran-3(6H)-one (0.01 mol) in 20 ml of acetic acid was treated with chlorine gas (0.01 mol) at room temperature. The reaction mixture was then heated to reflux for approx. 1 hour, cooled to room temperature, diluted with 20 ml of water, pH adjusted to 7.0 with 50% NaOH solution and the reaction mixture extracted with chloroform. The chloroform extract was concentrated to give maltol which was recrystallized from methanol to give the pure product (56%), m.p. 159.5 to 160.5°C.

Example 3

The procedure from example 2 was repeated, starting from a compound with the formula: where R is hydrogen, alkyl with 2 to 4 carbon atoms, phenyl or benzyl, R' is alkyl with 2 to 4 carbon atoms or -COR" where R" is methyl, ethyl or phenyl to give a gamma-pyrone of the formula:

where R is hydrogen, alkyl of 2 to 4 carbon atoms, phenyl or benzyl.

Example 4

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

Example, 5

The procedure from Example 2 was repeated with comparable results by 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)

1. Procedure for producing a gamma pyrone with the formula: where R is hydrogen or alkyl with 1 to 4 carbon atoms, and R<1>'<1> is hydrogen or alkyl with 1 to 4 carbon atoms, characterized in that a compound with the formula: where R and R" <1> are as indicated above, and R' is hydrogen, alkyl of 1 to 4 carbon atoms or -COR", where R" is methyl, ethyl or phenyl, is reacted in acidic aqueous solution with at least one equivalent of a halogen-containing oxidizing agent selected from chlorine, bromine, bromine chloride, hypochloric acidification, hypobromic acidification, or a mixture thereof, and the resulting 4-halo-dihydropyran intermediate is hydrolyzed by heating the reaction mixture. 2. Method according to claim 1, characterized in that the hydrolysis is carried out at a temperature in the range 70 to 160°C. 3. Method according to claim 1 or 2, for the production of 2-methyl-3-hydroxy-4H-pyran-4-one, characterized in that 6-methoxy-2-methyl-2H- pyran-3(6H)-one, aqueous acetic acid is used as an acidic solvent and gaseous chlorine is used as an oxidizing agent.