FI73424B - FOERFARANDE FOER FRAMSTAELLNING AV EN SOM MELLANPRODUKT VID 3-HYDROXI-4-PYRONFRAMSTAELLNINGEN ANVAENDBAR 4-HALOGEN- 6- (ALKOXI ELLER ALKANOYLOXI) -2,6-DIHYDRO-3-PYRON. - Google Patents

Description

1 73424

Process for the preparation of 4-halo-6- (alkoxy or alkanoyloxy) -2,6-dihydro-3-pyrone useful as an intermediate in the preparation of 3-hydroxy-4-pyrones 5 Separated from patent application 771934.

This invention relates to a process for the preparation of 4-halo-6- (alkoxy or alkanoyloxy-2,6-dihydro-3-pyrro-10) of formula (II1) useful as an intermediate in the preparation of 3-hydroxy-4-pyrones.

X

di ') R' O - O 2 '' X 15 wherein R is hydrogen or lower alkyl, R 'is lower alkyl or -COR ", wherein R" is lower alkyl and X is chlorine or bromine.

Maltol (2-methyl-3-hydroxy-4-pyrone) is a naturally occurring substance found in the bark of young larch, 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 (1974) 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) 30,998, 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.

35 batches of 6-methyl-2-ethyl-3-hydroxy-4-pyrone as a typical sweet-smelling ingredient obtained in the processing of molasses as 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.

Syntheses of 3-hydroxy-4-pyrones such as pyromeconic acid, maltol, ethyl maltol, 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, 3,365,459, 3,376,317, 3,468,915, 3,440,183 and 3,446,629.

10 Maltol and ethyl maltol increase the taste and aroma of various body supplies. In addition, these compounds are used as ingredients in perfumes and essences. The 2-alkenyl-lipyromeconic acids described in U.S. Patent No. 3,644,635 and the 2-arylmethylpyromeconic acids described in U.S. Patent No. 3,365,459 inhibit the growth of bacteria and fungi and are useful in flavor enhancers and flavor enhancers. as fragrance enhancers in perfumes.

20 In Paulsen, Eberstein and Koebernick,

Tetrahedron Letters 4377 (1974) discloses the synthesis of both optical forms of the trans isomer of both 4-chloro-ri- and 4-bromo-6-methoxy-2-methyl-2H-pyran-3 (6H) -one from a carbohydrate starting material.

Patent application 771934 discloses a process for the preparation of 3-hydroxy-4-pyrones of formula (I) 0 07 - wherein R is hydrogen, alkyl of 1 to 4 carbon atoms or benzyl, which process is characterized in that 4 to 35 halogen 2,6-dihydro-3-pyrone or 6,6'-oxy-bis / 4-halo-2,6-dihydro-3-pyrone.7 of formula (II),

II

3,73424

fV

I 1 (11)

R'cA 0 'R

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-halo-dihydropyranyl, and X is chlorine or bromine, hydrolyzed in an acidic aqueous solution at elevated temperature, preferably at 70-160 ° C, to give the compound of formula (I).

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 below.

The process according to the invention for the preparation of an intermediate of formula (II ') is characterized in that 6- (alkoxy or alkanoyloxy) -2,6-dihydro-3-pyrone of formula (IV) fr "

25 R10Ao ^ R

wherein R and R 'are as defined above, is reacted in a solvent at a temperature of -50 to + 50 ° C, preferably at room temperature, with at least one equivalent of a halogenated oxidant which is chlorine or bromine of formula (II') to the corresponding compound.

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 ί 73424 isopropyl ether, a low molecular weight ketone, preferably acetone, low molecular weight nitrile, ester or amide.

Some 4-halo-5- (alkoxy 5 or alkanoyloxy) -2,6-dihydro-3-pyrones of formula (II1) are novel compounds. These are compounds of formula (VI)

Jv »(VI) 10 R 4cT 0 NxC 2 H 5 4 wherein R is alkyl of 1-4 carbon atoms, or -COR" wherein R "is methyl or ethyl and X is chlorine or bromine, 4 provided that when X is chlorine R is not ethyl.

The starting material of formula (IV) can be prepared by reacting a furfuryl alcohol of formula (III)

R

wherein R is as defined above, to react in aqueous solution with at least one equivalent of a halogenated solvent selected from chlorine, bromine, bromine chloride, alichloroacid, alibromic 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 ') can be prepared directly from the appropriate furfuryl alcohol of formula (III) by reacting the latter in a solvent at -50 to + 50 ° C.

5,73424 with at least two equivalents of one of the aforementioned halogenated oxidants until the reaction is substantially complete.

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

The 6-alkoxy-2,6-dihydro-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-hydroxy-10-alkyl) -2,5-dialkoxy-dihydrofuran. Treatment with a strong organic acid provides the desired 6-alkoxy compound. The 6-alkanoyloxy compound can be prepared by treating the 6-hydroxy compound with a suitable anhydride in the usual manner in the presence of pyridine.

In one embodiment of the process, 6- (alkoxy or alkanoyloxy) -2,6-dihydro-3-pyrone is dissolved in a solvent which is water, ether, C 1 -C 4 alkanol or diol, or a low molecular weight ketone, nitrile, barrier -20 ri or amide. The most preferred solvent is methanol. One equivalent of a halogenated oxidant which is chlorine or bromine is added and 4-halo-6- (alkoxy or alkanoyloxy) -2,6-dihydro-3-pyrone is prepared and isolated by halogenation at -20 to + 20 ° C. , preferably at a temperature of 5 to 10 ° C, an organic base such as e.g.

in the presence of triethylamide. After about 30 minutes, the reaction mixture is allowed to warm to room temperature, filtered to remove triethylamide hydrochloride, and the solvent is removed in vacuo to give 4-halo-30-n-6- (alkoxy or alkanoyloxy) -2,6-dihydro-3-pyrone.

The following precursors describe the preparation of 4-halo-6- (alkoxy or alkanoyloxy) -2,6-dihydro-3-pyrones (II1).

In the examples where spectral data are reported, the values of the chemical shifts of the NMR spectra are given in 73424 6 by the symbolic symbols commonly used in the literature and all shifts are expressed in S units (from tetramethylsilane): s = singlet 5 d = doublet q = quartet Example 1 4-Chloro-6-methoxy-2-methyl-2,6-dihydro-3-pyrone To a solution of 6-methoxy-2-methyl-2,6-di-10-hydro-3-pyrone (0, 05 moles) in 70 ml of dichloromethane at -10 ° C was added chlorine (0.05 moles) via a gas inlet pipe. After this addition, triethylamine (0.05 mol) was added slowly keeping the temperature at -10 ° C. After stirring for 15-30 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 last residue was removed from triethylamine hydrochloride. Removal of the solvent gave 4-chloro-6-methoxy-2-methyl-2,6-dihydro-3-pyrone (99% yield). NMR analysis for signals 5.05-5.25 clearly showed the presence of two doublets in a ratio of 3: 1, corresponding to the 25 protons at C-6 of the two possible isomers of the compound.

Example 2 4-Bromo-6-methoxy-2-methyl-2,6-dihydro-3-pyrone The procedure of Example 1 was repeated by replacing chlorine with bromine to give 4-bromo-6-methoxy-2-methyl-2,6 -dihydro-3-pyrone in 93% yield. An NMR analysis result similar to that of the corresponding chlorine compound in the previous example was obtained for this bromine compound.

Example 3 4-Bromo-6-acetyloxy-2,6-dihydro-3-pyrone

A solution of 6-acetyloxy-2,6-dihydro-3-7,73424 pyrone prepared by the method described in Tetrahedron 27 (1971) 1973 in dichloromethane was brominated by the method of Example 2 to give 4- bromo-6-acetyloxy-2,6-dihydro-53-pyrone, m.p. 78-80 ° C. The mass spectrum of the compound had the expected parent peaks at mass units 234 and 236. Example 4 4-Bromo-6-acetyloxy-2-methyl-2,6-dihydro-3-pyrone The procedure of Example 3 was repeated using 6-acetyloxy-2-methyl-2,6-dihydro-3-pyrone to give 4-bromo-6-acetyloxy-2-methyl-2,6-dihydro-3-pyrone was obtained, with mass peaks in the mass spectroscopic assay at mass units 249.96 and 247.96 and the NMR spectrum was as follows: (<i (CDCl 3): 7.3 (1H, d); 6.4 (1 H, d-d); 4.7 (1 H, q); 2.2 (3 H, s); 1.4 (3 H, s).

Claims (1)

A process for the preparation of 4-halo-6- (alkoxy or alkanoyloxy) -2,6-dihydro-3-pyrone of formula (II ') X 1, which is useful as an intermediate in the preparation of 3-hydroxy-4-pyrones. II (II ') R 10 O 2 R 10 wherein R is hydrogen or lower alkyl, R' is lower alkyl or -COR ", wherein R" is lower alkyl and X is chlorine or bromine, characterized in that 6- (alkoxy or alkanoyloxy) -2,6-dihydro-3-pyrone of formula (IV) wherein R and R 'are as defined above are reacted in a solvent -50. .. at a temperature of + 50 ° C with at least one equivalent of a halogenated oxidant which is chlorine or bromine to give a compound of formula (II1).