FI72723C - Process for Preparation of 3-Hydroxy-4-Pyrones. - Google Patents

Description

72723

Process for the preparation of 3-hydroxy-4-pyrones Separated from patent application 771934.

The invention relates to a process for the preparation of 3-hydroxy-4-pyrones

of formula I

0> γ0Η 10 (I1 R is hydrogen or lower alkyl, by oxidation and hydrolysis of 6-hydroxy or 6-alkoxy-pyrone intermediates.

Main patent application 771934 relates to a process for the preparation of 3-hydroxy-4-pyrones by hydrolysis of certain intermediates prepared from suitable furfuryl alcohols using halogenated oxidants.

Maltol (2-methyl-3-hydroxy-4-pyrone) is a naturally occurring substance 20 found in the bark of young larch, pine needles and chicory. Previous technical manufacturing has taken place by dry distillation of wood. The flesh-lir. synthesis from 3-hydroxy-2- (1-piperidylmethyl) -1,4-pyrone is described by Spielman and Freifelder in J. Am. Chem. Soc., 69 (1947) 2908. Schenck and Spielman, J. Am. Chem. Soc., 67 (1945) 2276, obtained maltol by hydrolysis of streptomycin salts in alkaline solution. Chawla and McGonigal, J. Org. Chem., 39 (1974) 3281 and Lichtenthaler and Heidel, Angew. Chem., 81 (1969) 998, have described the synthesis of maltol from a protected carbohydrate derivative. Shono and Matsumura, Tetrahedron Letters No. 17, (1976) 1363, have described a five-step synthesis of maltol starting from methyl furfuryl alcohol.

The isolation of 6-methyl-2-ethyl-3-hydroxy-4-pyrone as a typical sweet-smelling ingredient in molasses processing is described by Hiroshi Ito in Article 2,72723 of Agr. Biol. Chem., 40 (5) (1976) 827-832. This compound had previously been synthesized by the method described in U.S. Patent 3,468,915.

The syntheses of 3-hydroxy-4-pyrones such as pyromeconic acid, maltone, ethyl maltone and other 2-substituted-3-hydroxy-4-pyrro-5s are described in U.S. Patent Nos. 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 increase the taste and aroma of various foods. In addition, these compounds are used as ingredients in perfumes and essences. The 2-alkenylpyromeconic acids described in U.S. Pat. No. 3,644,635 and the 2-arylmethylpyromeconic acids described in U.S. Pat. in fragrances.

Patent application 771934 discloses a process for the preparation of a 3-hydroxy-4-pyrone derivative by acid hydrolysis from a 3-pyrone derivative. In this case, 3-hydroxy-4-pyro-20-nin of formula (I ')

0C

Wherein R is hydrogen, alkyl of 1 to 4 carbon atoms, or benzyl, prepared from 4-halo-2,6-dihydro-3-pyrone or 6,6'-oxybis-3-halo-2,6-dihydro -3-pyrone / having formula (II) 30 «• Ä 35 3 72723 wherein R is hydrogen, alkyl of 1 to 4 carbon atoms, or Benzyl, R 'is hydrogen, lower alkyl, acetyl or optionally 2- (lower alkyl) substituted 4-halohydropyranyl, and X is chlorine or bromine.

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

The above compound of formula (II) can be prepared by reacting a compound of formula (IV) wherein R and R '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 oxidant selected from chlorine, bromine, bromine chloride, alachloric acid, alibromic acid or a mixture thereof until the reaction is substantially complete.

Examples of suitable solvents for use in this reaction include water, alkanol or diol having 1 to 4 carbon atoms, preferably methanol, ether having 2 to 10 carbon atoms, preferably tetrahydrofuran or isopropyl ether, a low molecular weight ketone, preferably acetone, low molecular weight nitrile, ester or amide.

The above intermediate of formula (IV) can be prepared by reacting a furfuryl alcohol of formula (III) 1 H 2 (III) 4 72723 wherein R is as defined above with at least one equivalent of a halogenated oxidant selected from chlorine, bromine, bromochloride, alachloric acid, sub-bromic acid or a mixture thereof, at a temperature of -50 to + 50 ° C, preferably at room temperature, until the reaction is substantially complete. The reaction may be carried out in the presence of an additional solvent, which may preferably be one of the aforementioned solvents used in the preparation of the intermediate of formula (II).

If desired, the 4-halo-dihydropyran intermediate of formula (II) may be prepared directly from the appropriate furfuryl alcohol of formula (III) by reacting the latter in a solvent at -50 to + 50 ° C with at least two equivalents of any of the above. halogenated oxidant until the reaction is substantially complete.

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

The process according to the invention for the preparation of 3-hydroxy-4-pyrones of the formula (I) is characterized in that the 2,6-dihydro-3-pyrone of the formula (IV) 1 λ (iv)

25 R10 0 "^ R

wherein R is as defined above and R 'is hydrogen or lower alkyl, is reacted in an acidic aqueous solution which is aqueous acetic acid with at least one equivalent of a halogenated oxidant which is chlorine and the reaction mixture is heated to give the resulting 4-halo-dihydropyran intermediate. to hydrolyze substantially completely.

In a preferred embodiment of the process according to the invention, the compound of formula (IV) is 6-methoxy-2-methyl-3-pyrone, the oxidant is chlorine and the resulting product is 2-methyl-3-hydroxy-4-pyrone.

5,72723

The 6-alkoxy-3-pyrone of formula (IV) can be prepared by the method described in Tetrahedron Letters No. 17 (1976) 1363-1364. Furfuryl alcohol is anodized to 2- (1-hydroxyalkyl) -2,5-dialkoc-5-dihydrofuran. Treatment with a strong organic acid provides the desired 6-alkoxy compound.

The 6-alkoxy-3-pyrone is dissolved in a solvent, which is preferably acetic acid. One equivalent of a halogenated oxidant which is chlorine is added at room temperature and the reaction mixture is heated at 70-160 ° C, usually 100-110 ° C until the conversion to the desired 3-hydroxy-4-pyrone is substantially complete (ca. 1-3 hours). 4-Pyrone can be recovered from the cooled, neutralized reaction mixture after it is in place, or a new 15 ml reaction mixture can be recovered as a solvent, e.g., chloroform, obtained by concentrating 3-hydroxy-4-pyrone.

This process, in which 6-alkoxy-3-pyrone is reacted in an organic solvent with one equivalent of a halogenated oxidant and the 4-20 halo-dihydropyran intermediate formed in situ is heated until the conversion to the desired 4-pyrone is substantially complete, differs from the multi-step process of described by Shono and Matsumura in Tetrahedron Letters 17 (1976) 1363, in which 6-alkoxy-3-pyrone is treated with a methanolic solution of hydrogen peroxide with a solution of sodium hydroxide to give an epoxy ketone. The isolated epoxy ketone is heated to reflux in water with Dowex 50 ion exchange resin to give the desired 3-hydroxy-4-pyrone.

The following features describe the preparation of 3-hydroxy-4-pyrones by the process of this invention.

In the examples where spectral data are reported, the values of the chemical shifts of the NMR spectra are given by the symbolic symbols commonly used in the literature and all shifts are expressed in ε units (from tetramethylsilane): 6 72723 s = singlet d = doublet t = triplet q = quartet 5 m = multiplet br = broad Preparation of starting materials a) 6-hydroxy-2-methyl-3-pyrone

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 one equivalent of bromine. The temperature was maintained between 5 and 10 ° C throughout the addition. The pH of the solution was adjusted to 2.1 and extracted with ethyl acetate (3 x 50 mL). The ethyl acetate extract was dried and evaporated to dryness 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 to be identical in spectral values. -hydroxy-2-methyl-3-pyrone prepared from 6-methoxy-2-methyl-3-pyrone by acid hydrolysis / Tetrahedron 27 (1971) 19737.

IR (CHCl 3) 3700, 3300, 1700 cm -1 NMR (CDCl 3, δ); 6.8-7.1 (1H, dd); 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 procedure of a) was repeated using furfuryl alcohol of formula 1

CV0H

R

to give a compound of formula 7 72723 fr H 2 O 0 Ar 5 wherein R is hydrogen or ethyl.

Ethyl compound: IR (CHCl 3, 3600, 3340, 1706 cm -1 J -1

Hydrogen compound: IR (CHCl 3 3565, 3300, 1703 cm -1

Example 1 2-Methyl-3-hydroxy-4-pyrone

A solution of 6-methoxy-2-methyl-3-pyranone (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 about 1 hour, cooled to room temperature, diluted with 20 mL of water, adjusted to pH 7.0 with 50% NaOH solution, and extracted with chloroform. The chloroform extract was concentrated to give the title product, which was recrystallized from methanol to give 20 pure products (yield 56%), m.p. 159.5-160.5 ° C.

Example 2

The procedure of Example 1 was repeated, but starting from 0.01 mole of a compound of formula R'0 R 1 2 3 4 5 6 wherein R is hydrogen or alkyl of 2-4 carbon atoms and 2 R 'is alkyl wherein has 2 to 4 carbon atoms. This was treated with 3 0.01 moles of chlorine gas at room temperature, after which the reaction mixture of 4 was treated as described in Example 1 to give 3-hydroxy-4-pyrone of formula 72723 8

O

0H 1 Ψ

AR ° C

5 wherein R is hydrogen or alkyl of 2 to 4 carbon atoms. Melting points of the final products: R mp (° C) H 117-118 10 C2H5 90 C3H? 82-83 C4H9 55-56

Claims (3)

9,72723 A process for the preparation of 3-hydroxy-4-pyrones of formula (I) 5 O OH f Ϊ (I) V o ^ R (±) 10 wherein R is hydrogen or lower alkyl, characterized in that 2,6-dihydro-3-pyrone of formula (IV) R '(Ao ^ r (IV) wherein R is as defined above and R' is hydrogen or lower alkyl is reacted in an acidic aqueous solution which is aqueous acetic acid with at least one equivalent of a halogenated oxidant which is chlorine and the reaction mixture is heated to substantially completely hydrolyze the resulting 4-halo-dihydropyran intermediate. Process according to Claim 1, characterized in that the hydrolysis temperature is 70 to 160 ° C. Process for the preparation of 2-methyl-3-hydroxy-4-pyrone according to Claim 1 or 2, characterized in that the compound of formula (IV) is 6-methoxy-2-methyl-3-pyrone and the oxidant is chlorine gas.