FI72722B - FOER FARING FRAMSTAELLNING AV 3-HYDROXI-4-PYRONER. - Google Patents

Description

rB1 nn ADVERTISEMENT 7 9 7 0 0 • $ 81? ^ UTLÄGGNINGSSKRIFT ΙΙΙΖλ c Patent n.ycnnc tty '} Patent meddelat 10 07 1037 (51) Kv.lk//lnt.a.' C 07 D 309 / ^ 0 FINLAND FINLAND (2.1) Patent application - Patentansöknlng 77193 * + (22) Application line - Ansökningsdag 21 .06.77 (23) Initial line - Giltighetsdag 21.06.77 (41) Become a public sex - Blivit offentlig 03.02.78

National Board of Patents and Registration Date of publication and publication. -

Patents and registration documents' 1 Ansökan utlagd och utl.ikriften publlcerad 31 .03.87 (86) Kv. application - Int. ansökan (32) (33) (31) Privilege requested - Begird priority 02.08.76 09.09.76 USA (US) 7IO9OI, 721885 (71) Pfizer Inc., 235 East * i2nd Street, New York, New York, USA (US) ) (72) Thomas Mott Brennan, Old Lyme, Connecticut,

Daniel Patrick Brannegan, Pawcatuk, Connecticut,

Paul Douglas Weeks, Gales Ferry, Connecticut,

Donald Ernest Kuhia, Gales Ferry, Connecticut, USA (7 * 0 Oy Koi ster Ab (5 * 0 Method for the preparation of 3-hydroxy- * t-pyrones -Förfarande för framstä11 Ning av 3-hydroxy-A-pyroner

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

wherein R is hydrogen, alkyl of 1 to 4 carbon atoms, or benzyl.

Maltol (2-methyl-3-hydroxy-4-pyrone) is a naturally occurring substance found in the bark of young larch trees, pine needles, and chicory. Previous technical manufacturing has taken place by dry distillation of wood. The synthesis of maltol from 3-hydroxy-2- (1-piperidylmethyl) -1,4-pyrone has been 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 72722 wheat 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 protected carbohydrate derivatives. 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-scented ingredient in molasses processing is described by Hiroshi Ito in 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, maltol, ethyl limaltol and other 2-substituted-3-hydroxy-4-pyrones are described in U.S. Patent Nos. 3,130,204, 3,133,089, 3,140,239, 3,159,652. , 3,465,469, 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. .

The process according to the invention for the preparation of the 3-hydroxy-4-pyrones of the formula I is characterized in that 4-halo-2,6-dihydro-3-pyrone or 6,6'-oxy-bis-4-halo-2 , 6-dihydro-3-pyrone / of formula (II)! ii R 0 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-halodihydropyranyl, and X is chlorine 3,72722 or bromine, is hydrolysed in an acidic aqueous solution at an elevated temperature, preferably at 70-160 ° C, to give a compound of formula (I).

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

An intermediate of formula (II) wherein R 'is hydrogen, lower alkyl or acetyl, and R is hydrogen, alkyl of 1 to 4 carbon atoms, or benzyl can be prepared by reacting a compound of formula (IV) i iv

R '0' ^ Sn0 /> X'R

wherein R and R 1 are as defined in formula II, to react in a solvent at a temperature of -50 ° C to + 50 ° C, preferably at room temperature, with at least one equivalent of a halogen-containing anoxic substance which is chlorine, bromine, bromine chloride, alachloric acid, aliquot bromic 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, a low molecular weight nitrile, ester or amide.

The above intermediate of formula (IV) can be prepared by reacting a furfuryl alcohol of formula (III) wherein R is as defined above with at least one equivalent of a halogenated oxidant selected from chlorine, bromine, bromochloride, alachloric acid, alibromic acid or a mixture thereof at a temperature of -50 ° C 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) can be prepared directly from the appropriate furfuryl alcohol of formula (III) by reacting the latter in a solvent at -50 ° C. . ·. At a temperature of + 50 ° C with at least two equivalents of one of the abovementioned halogenated oxidants until the reaction is substantially complete.

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

An intermediate of formula (II) wherein R 'is optionally 2- (lower alkyl) substituted 4-halo-dihydropyranyl and R is hydrogen, alkyl of 1 to 4 carbon atoms, or benzyl can be prepared by cleavage of water from a compound of formula (II ')

X

II "wherein R is as defined above and X is chlorine or bromine.

The process of the invention can be described, for example, by the following reaction formula in which the preparation of a compound of formula (I) is described starting from a compound of formula (III) when R is hydrogen, alkyl of 1 to 4 carbon atoms or benzyl; and X is Cl or Br: 5 x 72722) 6r—

0H OH N R OH R

u ti H — 0 = 0 open chain tautomer

CH

C = O

H —COH

R

x? \

0 ^ ° H

/ \ Ab δ ν, Λ 0H U.

lv II 'open chain tautomer

In an article, Lefebvre and colleagues presented in J. Med. Chem. 16 (1973) 1084 that furfuryl alcohols can be converted directly to 6-hydroxy-2,6-dihydro-3-pyrones using a peracid oxidant such as peracetic acid or m-chloroperbenzoic acid. In the first step of the Le-febvre procedure, peracid is used in an organic solvent and probably results in the formation of a 6-acetoxy or 6-m-chlorobenzoyloxypyran derivative which is hydrolyzed to the 6-hydroxy compound upon further treatment with water.

In the first stage of the reaction, no water is used and it would actually be harmful. In any case, the method of Lefebvre and 6,72722 co-workers cannot directly lead to the conversion of furfuryl alcohol to 3-hydroxy-4-pyrone.

Crucial in the process for the preparation of intermediates of formula (II) is the use of an aqueous solution of a halogenated oxidant. Furfuryl alcohol can be oxidized to pure 6-hydroxy-2,6-dihydro-3-pyrone using one equivalent of a halogenated oxidant in water or a mixture of water and an additional organic solvent. It is surprising and unexpected to find that 6-hydroxy-2,6-dihydro-3-pyrones can be converted to 3-hydroxy-4-pyrones. 6-Hydroxy-2,6-dihydro-3-pyrone can be considered an aldehyde hemiacetal and as such could be expected to be involved in a number of undesirable side reactions, such as oxidation reactions or aldol-type condensation reactions. Using two equivalents of a halogenated oxidant in water or a mixture of water and an additional organic solvent, the reaction proceeds steadily from furfuryl alcohol to 3-hydroxy-4-pyrone. This new one-pot process offers the advantageous possibility of using low-cost Cl 2, Br 2, BrCl, HOCl, HOBr or mixtures thereof as the halogen-containing oxidant. Isolation of the desired 3-hydroxy-4-pyrone is greatly simplified because the solvent, oxidant, and by-product inorganic acid are all volatile and can be removed in vacuo to give crude 3-hydroxy-4-pyrone directly in maximum yields by concentration alone.

The operation in one vessel is carried out by dissolving furfuryl alcohol in water or water and co-solvent. The co-solvent may be water-miscible or water-immiscible and may be selected from a variety of solvents which may be, for example, C 1 -C 4 alkanols or diols, for example methanol; ethers, for example tetrahydrofuran or isopropyl ether; low molecular weight ketones, for example acetone; low molecular weight nitriles; low molecular weight amides. Preferred co-solvents are C 1 -C 6 alkanols and C 1 -C 1 ethers, with methanol being the most preferred solvent. The temperature of the solution Δ 'υ 0 0 is kept between -50 ° C and + 50 ° C, preferably between -10 ° C and + 10 ° C. To this solution is added the desired furfuryl alcohol 7,72722 by simultaneously adding a halogenated oxidant (two equivalents) to the reaction mixture. The temperature of the reaction mixture is maintained at -50 ° C during the addition of halogen. At + 50 ° C, preferably -1 0 ° C. . At + 10 ° C. If a low boiling co-solvent is used, it is removed by distillation after all additions have been made. The reaction mixture is then heated to a temperature at which the hydrolysis takes place at a reasonable rate, for example 70 ° C to 160 ° C. The commonly used hydrolysis temperature is 100 ° C to 110 ° C. Heating is continued until the hydrolysis of the formed 4-halo-dihydropyran intermediate is substantially complete (usually 1-2 hours). The acid required for this final hydrolysis is evolved in situ upon release of the acid from the intermediates formed during the reaction. If desired, more acid can be added.

The halogen-containing oxidant is chlorine, bromine, bromochloride, alachloric acid or alibromic acid or a mixture thereof. Bromine chloride is a gas obtained as a technical product. 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. Ali-chloroacid and alibromoacid can be conveniently prepared in situ by adding an aqueous solution of the acid (HCl, or HBr) to an alkali metal or alkaline earth metal hypohalite, e.g., a solution of NaOCl, KOCl, or CatOCl 2. Preferred halogen-containing oxidants are chlorine and bromochloride prepared in situ.

As described above, the 6-hydroxy-2,6-dihydro-3-pyrone intermediate of formula (IV) can be prepared by reacting the appropriate furfuryl alcohol with one equivalent of a halogenated oxidant. The isolated intermediate can be readily converted to the desired 3-hydroxy-4-pyrone by reacting it with another halogen oxidant equivalent and hydrolyzing the resulting 4-halo-6-hydroxy-2,6-dihydro-3-pyrone of formula (II) as previously described. .

Alternatively, the furfuryl alcohol may be reacted in an aqueous solution with an optional co-solvent at -10 ° C to + 10 ° C with two equivalents of a halogenated oxidant. After stirring for 30 minutes at room temperature, the reaction mixture is adjusted to pH 2 with a strong base and the reaction mixture is extracted with a solvent such as ethyl acetate. Removal of the solvent gives 4-halo-6-hydroxy-2,6-dihydro-3-pyrone of formula (II ') which can be hydrolysed to the desired 3-hydroxy-4-pyrone. Water can be cleaved from 4-halo-dihydropyran by heating in vacuo to give 6,6'-oxy-bis (4-halo-2,6-dihydro-3-pyrone). This dimer is obtained by hydrolysis of the desired 3-hydroxy-4-pyrone, with the addition of an acid if desired.

In the following, Preparations 1-11 describe the preparation of various intermediates and Examples 1-6 describe the preparation of 3-hydroxy-4-pyrones by the process of this invention.

In preparations and 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 ^ units (from tetramethylsilane): s = singlet d = doublet t = triplet q = quartet m = multiplet br = wide

Preparation 1 6-Hydroxy-2-methyl-2,6-dihydro-3-pyrone (Formula IV)

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 5-10 ° 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 by spectral values to be identical to 6 72722 with hydroxy-2-methyl-2,6-dihydro-3-pyrone prepared from 6-methoxy-2-methyl-2,6-dihydro-3-pyrone by acid hydrolysis (Tetrahedron 27 (1971) 1973).

IR (CHCl 3) 3700, 3300, 1700 cm -1 NMR (CDCl 3 δ): 6.8-7.1 (1H, d of d); 6.0-6.2 (1H, d), 5.6 (1H, br. S, exchanged with D 2 Orn), 5.4-5.5 (1H, d), 4.8-5.0 (1H, q), 1.3-1.6 (3H, t).

Preparation 2

The procedure of Preparation 1 was repeated, in which one equivalent of bromine was added to a solution of furfuryl alcohol in 125 ml of tetrahydrofuran and 125 ml of water at 5 ° C, but using a furfuryl alcohol compound of formula

R

wherein R is hydrogen or ethyl.

The temperature was maintained between 5-10 ° 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 the corresponding compound of formula

IV

HO O R

wherein R is hydrogen or ethyl.

Ethyl compound: IR (CHCl 3) 3600, 3340, 1706 cm -1 6 Hydrogen compound: IR (CHCl 3) 3565, 3300, 1703 cm

Preparation 3 4-Bromo-6-hydroxy-2-methyl-2,6-dihydro-3-pyrone (Formula II) To a solution of 25 g of 1- (2-furyl) -1-ethanol in 125 ml of tetrahydrofuran and 125 ml of water at 0-5 ° C, 2.2 equivalents of bromine were added dropwise. The temperature was maintained between 5-10 ° C throughout the addition. After the addition of bromine, the solution was stirred at room temperature for 30 minutes and the pH was adjusted to 2.1 with 2 N NaOH solution. The reaction mixture was extracted with ethyl acetate (3 x 100 mL). The ethyl acetate extracts were combined, dried over MgSO 4, filtered and evaporated to dryness. The residue was chromatographed on silica gel eluting with chloroform-ethyl acetate (95: 5). The product was an orange oil which was rechromatographed on silica gel eluting with chloroform-ethyl acetate (95: 5).

NMR (CDCl 3, δ) 7.3 (1H, d); 5.6 (1 H, d)? 4.7-5.0 (1 H, q); 1.1-1.5 (3 H, m).

Preparation 4

The procedure of Preparation 3 was repeated, to which a solution of furfuryl alcohol in 125 ml of tetrahydrofuran and 125 ml of water at 0-5 ° C was added dropwise with 2.2 equivalents of bromine, but using the compound of formula

Or "

° R

wherein R is hydrogen or ethyl.

The temperature was maintained between 5-10 ° C throughout the addition. After the addition of bromine, the solution was stirred at room temperature for 30 minutes and the pH was adjusted to 2.1 with 2 N NaOH solution. The reaction mixture was extracted with ethyl acetate (3 x 100 mL). The ethyl acetate extracts were combined, dried over MgSO 4, filtered and evaporated to dryness. The residue was chromatographed on silica gel, eluting with chloroform-ethyl acetate (95: 5). The product was an oil which was rechromatographed on silica gel eluting with chloroform-ethyl acetate (95: 5). Corresponding to the starting material, a compound of formula 11 was obtained

II

72722 ηο '/ Ν ^ 0 "\ r wherein R is hydrogen or ethyl and X is bromine.

Ethyl compound: 4-bromo-6-hydroxy-2-ethyl-2,6-dihydro-3-pyrone NMR (CDCl 3, δ) 7.4 (1H, d); 4.6-4.9 (1 H, m); 1.8-2.2 (2 H, m); 1.0-1.3 (3 H, t).

Hydrogen compound: 4-bromo-6-hydroxy-2,6-dihydro-3-pyrone NMR (CDCl 3, f) 7.4 (1H, d); 5.5 (1 H, d); 4.6 (2H, d of d). Preparation 5

The procedure of Preparation 3 was repeated using chlorine instead of bromine and, as furfuryl alcohol, a compound of formula

(K

X0 R

wherein R is in each case methyl, ethyl or hydrogen. Accordingly, the following compounds of formula (II) were obtained:

Methyl: 4-chloro-6-hydroxy-2-methyl-2,6-dihydro-3-pyrone NMR (CDCl 3, cT): 7.1 (1H, d); 5.8 (1 H, d); 4.6-5.0 (1 H, m); 4.4 (1H, br.s.); 1.2-1.5 (3 H, m).

Ethyl: 4-chloro-6-hydroxy-2-ethyl-2,6-dihydro-3-pyrone NMR (CDCl 3, (f); 7.0-7.1 (1H, d); 5.6-6, O (2H, m), 4.4-5.0 (1H, m), 1.6-2.1 (2H, m), 0.9-1.1 (3H, t) Hydrogen: 4- chloro-6-hydroxy-2,6-dihydro-3-pyrone NMR (CDCl 3 R 5) '7.1-7.2 (1H, d); 5.6 (1H, d); 4.4-4.9 ( 2H, d of d) (D20 added).

Preparation 6 4-Bromo-6-hydroxy-2-methyl-2,6-dihydro-3-pyrone was heated in vacuo at 40 ° C for 16 hours. The resulting oily solid was crystallized from isopropyl alcohol to give 6,6'-oxy-bis- (4-bromo-2-methyl-2,6-dihydro-3-pyrone), m.p. 125 ° C.

Preparation 7

The procedure of Preparation 6 was repeated by heating the compound of formula in vacuo for 16 hours at 40 ° C

Cl (A ^ °

CR ^ R

wherein R is methyl or ethyl. The resulting oily solid was crystallized from isopropyl alcohol to give a compound of formula J'1 Cl2 wherein R is methyl or ethyl.

R Sp. (° C) CH 3 177 ° -179 ° CH 2 CH 3 132 ° -135 °

Preparation 8 4-Chloro-6-methoxy-2-methyl-2,6-dihydro-3-pyrone (Formula II) To a solution of 6-methoxy-2-methyl-2,6-dihydro-3-pyrone (0.05 mol) In 70 ml of dichloromethane at -10 ° C, chlorine (0.05 mol) was added via a gas inlet pipe. After this addition, triethylamine (0.05 mol) was added slowly keeping the temperature at -10 ° C. After stirring for 30 minutes, the reaction mixture was allowed to warm to room temperature, filtered to remove triethylamine hydrochloride and the solvent removed in vacuo. By redissolving the crude product in ether-benzene and filtering, the final residues were removed from triethylamine hydrochloride. Removal of the solvent gave 4-chloro-6-methoxy-2-methyl-2,6-dihydro-3-pyrone (99% yield).

72722 13 NMR analysis at signals 5.05-5.25 clearly showed the presence of two doublets in a ratio of 3: 1, corresponding to the proton at C-6 of the two possible isomers of the compound. Paulsen, Eberstein, and Koebernick, Tetrahedron Letters 4377 (1974), had synthesized both optical forms of the trans isomer from the carbohydrate starting material.

Preparation 9 4-Bromo-6-methoxy-2-methyl-2,6-dihydro-3-pyrone (Formula II)

The procedure of Preparation 8 was repeated replacing chlorine with bromine to give 4-bromo-6-methoxy-2-methyl-2,6-dihydro-3-pyrone in 93% yield. Paulsen and colleagues had synthesized two optical forms of the trans isomer, Tetrahedron Letters 4377 (1974).

Preparation 10 4-Bromo-6-acetoxy-2,6-dihydro-3-pyrone (Formula II)

A solution of 6-acetoxy-2,6-dihydro-3-pyrone prepared by the method described in Tetrahedron 27, (1971) 1973 in dichloromethane was brominated by the method of Example 5 to give 4-bromo- 6-acetoxy-2,6-dihydro-3-pyrone, m.p. 78 ° -80 ° C. The mass spectrum of the compound had the expected peaks of origin at mass units 234 and 236.

Preparation 11 4-Bromo-6-acetoxy-2-methyl-2,6-dihydro-3-pyrone (Formula II)

The procedure of Preparation 10 was repeated using 6-acetoxy-2-methyl-2,6-dihydro-3-pyrone to give 4-bromo-6-acetoxy-2-methyl-2,6-dihydron-3-pyrone having a mass of -spectroscopic assay had origin peaks at mass units 249.96 and 247.96 and the NMR spectrum was as follows: (<f, CDCl 3): 7.3 (1H, d); 6.4 (1H, d of d); 4.7 (1 H, Q); 2.2 (3 H, S); 1.4 (3 H, s).

Example 1 2-Methyl-3-hydroxy-4-pyrone (Formula I)

A solution of 4-bromo-6-hydroxy-2-methyl-2,6-dihydro-3-pyrone was prepared by dissolving the compound in either aqueous inorganic or aqueous organic acid. The solution was then heated to reflux, cooled to room temperature, adjusted to pH 2.1 with 6 N NaOH, and extracted with chloroform. Concentration gave the title product, m.p. 160 ° C. The yields of acids, reaction time and 2-methyl-3-hydroxy-4-pyrone were as follows:

Acid_Concentration (%) _ Reaction time (s) Yield (%) HCl 32 2 68 HCl 32 5 52 HCl 18 5 35 HCl 25 3 49 HBr 18 5 24 H 2 SO 4 35 2 26 H 3 PO 4 35 2 29 CH 3 COOH 35 2 69 CF 3 COOH undiluted 3 36 HNO 3 35 3 0.4 CF3COOH undiluted 3 70 CH3COOH undiluted 3 77 HCOOH undiluted 3 24 H2SO4 35 5 48

Alternatively, organic solvents such as benzene and toluene may be used in combination with acidic substances such as p-toluenesulfonic acid and "Amberlite" IR-120.

Example 2 2-methyl-3-hydroxy-4-pyrone

A solution of 4-bromo-6-hydroxy-2-methyl-2,6-dihydro-3-pyrone (0.0025 mol) in 20 ml of 35% phosphoric acid was boiled for about five hours. The title product was isolated by filtering the reaction mixture while hot, cooling, adjusting the pH to 2.2 and cooling the reaction mixture to 5 ° C. Crystallization and filtration gave crude 3-hydroxy-2-methyl-4-pyrone. The aqueous filtrate was extracted with chloroform to give a second crop of maltol. Distillation of the combined solids and recrystallization from methanol gave the title product (35%) as a pure white solid, m.p. 159.5 to 150.5 ° C.

72722 15

Example 3

A solution of 0.0025 moles of the compound of formula

X X

° \ Jk ^ O

Wherein R is in each case hydrogen, methyl, ethyl, propyl, butyl or benzyl; and X is bromine or chlorine, was boiled according to Example 2 in 20 ml of 35% phosphoric acid for about five hours. In each case, a compound of the formula was obtained

O

f Γ

^ O ^ R

wherein R is as defined above and which was isolated according to Example 2. The obtained compounds had the following melting points: R Sp. (° C) H 117-118 CH3 160 C2H5 90 C3H7 82-83 C4H9 55-56

CcHcCH0 142-143 6 5 2

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

To a round-bottomed flask equipped with a stirrer and condenser were added 4-chloro-6-methoxy-2-methyl-2,6-dihydro-3-pyrone and acetic acid, and the reaction mixture was heated at reflux for 1 hour. On cooling, the title product (65%) was obtained.

Example 5 2-methyl-3-hydroxy-4-pyrone

The procedure of Example 4 was repeated using 72722 16 formic acid instead of acetic acid. The title product was obtained in 65% yield with comparable results.

Example 6

The procedure of Example 4 was repeated using a compound of formula II as starting material

X

II

r, oAo / xr wherein R is in each case hydrogen, alkyl of 1 to 4 carbon atoms or benzyl; R 'is alkyl of 1 to 4 carbon atoms or -COR ", wherein R" is methyl or ethyl and X is bromine or chlorine. The starting material and acetic acid were added to a round bottom flask equipped with a stirrer and condenser. The reaction mixture was heated to reflux for one hour. Cooling gave a compound of formula

OH

wherein R is hydrogen, alkyl of 1 to 4 carbon atoms or benzyl.

The obtained compound had the following melting points: R Sp. (° C) H 117-118 CH 3 160 C 2 H 5 90 C 3 H? 82-83 C4H9 55-56 0, -Hj.CH 142-143 6 o 2

Claims (1)

A process for the preparation of 3-hydroxy-4-pyrones of formula (I) wherein R is hydrogen, alkyl of 1 to 4 carbon atoms or benzyl, characterized in that 4-halo-2, 6-dihydro-3-pyrone or 6,61-oxy-bis / 4-halo-2,6-dihydro-3-pyrone of formula (II) X r, ° wherein R is hydrogen, alkyl , having 1 to 4 carbon atoms, or benzyl, R 'is hydrogen, lower alkyl, acetyl or optionally 2- (lower alkyl) substituted 4-halodihydropyranyl, and X is chlorine or bromine, is hydrolysed in an acidic aqueous solution at elevated temperature, preferably 70 At -160 ° C to give the compound of formula (I).