HU186026B - Process for preparing 4-halo-dihydro-pyran-3-one derivatives - Google Patents

Abstract

The gamma-pyrones of formula I in which the symbols have the meaning given in Claim 1 are obtained by a simple and economic "one-pot" process by reaction of a furfuryl alcohol of formula III with at least 2 equivalents of a halogenated oxidising agent, in aqueous solution at a temperature of between -50 DEG and +50 DEG C, and then the reaction mixture is heated until hydrolysis of the intermediate formed is virtually complete. The gamma-pyrones obtained can be used as products which enhance flavour and fragrance in food and cosmetic preparations. <IMAGE>

Description

The present invention relates to a process for the preparation of 4-halo-dihydropyran-3-one derivatives which are valuable intermediates.

Malt (2-methyl-3-hydroxy-4H-pyran-4-one) is a naturally occurring substance found in the bark, needles and chicory of young larch. Previously, it was produced by the destructive distillation of wood.

The synthesis of Mattol from 3-bidroxy-2- (1-piperidinylmethyl) -1,4-pyrone is described by Spielman and Freifelder in J. Am. Chem. Soc., 69, 2908 (1947). Schenck and Spielman, J. Am. Chem. Soc., 67, 2276 (1945), describe the synthesis of 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) describes the synthesis of protected carbohydrate derivatives from May. Shono and Matsumura, in Tetrahedron Letters No. 17, 1363 (1976), disclose a five-step process for the preparation of maltol starting from methylfurfuryl alcohol.

6-methyl-2-ethyl-3-hydroxy-4H-pyran-4-one, which is described in Hiroshi lto, an aroma component isolated during purification of molasses [Agr. Biol. Chem. 40 (5): 827-832 (1976)]. This compound is disclosed in U.S. Pat. U.S. Pat.

Gamma-pyrones. thus pyromeconic acid. maltol. for the synthesis of ethylmaltol and other 2-substituted 3-hydroxy-gamma-pyran derivatives, see U.S. Patent 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. U.S. Pat.

Milk and ethyl maltol enhance the aroma and aroma of various food products. In addition, these compounds are also used as fragrances in perfumes and perfumes. For 2-alkenylpyromeconic acids, see U.S. Patent 3,644,635. 2-Arylmethylpyromeconic acids are disclosed in U.S. Pat. U.S. Patents Nos. 4,677,125 and 5,127,125 disclose that they inhibit the growth of bacteria and fungi, and also have flavoring and food-improving substances, as well as flavoring agents in beverages and perfumes.

Hungarian Patent No. 180,040 relates to a process for the preparation of 3-hydroxy-gamma-pyrone derivatives of the formula (111), which is acidic. in an aqueous solution, preferably at a temperature in the range of from 70 ° C to 160 ° C, the 4-halohydro-pyranone derivative of formula (I) is heated to substantially complete hydrolysis. In the formulas:

R is hydrogen, (C1-C4) -alkyl, phenyl or benzyl,

R 'is hydrogen, (C 1 -C 4) -alkyl or -COR, wherein R' is methyl, ethyl or phenyl.

R '' 'is hydrogen or (1-4C) alkyl, and

X is chlorine or bromine.

The 4-halo dihydropyran-3-one derivatives of the present invention represented by formula (I) are either hydrogen or (C 1 -C 4) -alkyl, R '(C 1 -C 4) -alkyl or a group -COR' wherein

R 'is methyl or ethyl, and

X is chlorine or bromine.

The intermediates of formula (I) are prepared as follows. that of formula (II) wherein R and R 'are as defined for formula (I) in a solvent - is reacted with at least one equivalent of chlorine or bromine at 50 ° C and ⁶ to 50 C stone Zotti temperature.

Suitable solvents for the reaction are water. C 1 -C 4 alkanols or diols, preferably methanol, C 2 -C 10 ethers, preferably tetrahydrofuran or isopropyl ether. low molecular weight nitriles, esters or amides.

The intermediates of formula (II) may be prepared by diluting an aqueous solution of a furfuryl alcohol derivative of formula (IV) wherein R is as defined above and R '' is hydrogen, with at least one equivalent of chlorine, bromine, with bromochloride, hypochlorous acid. hypobromo-wash or mixtures thereof. that is, the halogen-containing oxidant is reacted at a temperature of -50 ° C to 50 ° C, preferably room temperature, until the reaction is complete. The reaction may also comprise the use of an auxiliary solvent, such as one of the solvents mentioned in the preparation of the intermediates of formula (I).

If desired, the 4-halo-dihydropyran compound of formula (I) may also be prepared directly from a suitable furfuryl alcohol derivative of formula (IV) by reacting the latter with at least two equivalents of one of the halogen-containing oxidizing agents listed above. .

As mentioned above, the intermediate 6-hydroxy-2H-pyran-3 (6H) -one (II) can be prepared by reacting the corresponding furfuryl alcohol with an equivalent amount of a halogen-containing oxidant. The isolated intermediate is reacted with an additional equivalent amount of a halogen-containing oxidant to give 4-halo-6-hydroxy-2H-3 (6H) -one of formula (I).

6-Alkoxy-2H-pyran-3 (6H) -one is described in Tetrahedron Letters 17, 1363-1364 (1976). can be prepared as described in the literature. Some furfuryl alcohol derivative is anodically alkoxylated to give? - (1-Hydroxyalkyl) -2,5-dialkoxy dihydrofuran is treated with a strong organic acid to give the desired 6-alkoxy compound. The 6-acyl compound can be prepared by treating the appropriate 6-alkoxy compound with the appropriate anhydride in the conventional manner in the presence of pyridine.

The 6-acyl or 6-alkoxy-2H-pyran-3 (6H) -one derivative in acetic acid, formic acid, trifluoroacetic acid, in a halogenated solvent, in ether, C 1 -C 4 alcohol or in nuts, in a low molecular weight ketone, · in nitrile , in an ester or atnid. Preferred solvents are formic acid and methanol. Chlorine bromine, bromochloride, hypochlorous acid, hypobromic acid, or a mixture thereof, is added to the reaction mixture at room temperature until the desired conversion is effected.

If desired, the 4-halo-dihydropyran can be prepared and isolated by halogenation at a temperature of -20 ° C to 20 ° C, preferably 5 ° C to 10 ° C, in the presence of an organic base such as triethylamine. After 30 minutes, the reaction mixture was allowed to warm to room temperature, then filtered to remove the triethylamine and filtered. the solvent was removed in vacuo. This gives the 4-halo-dihydropyran.

The following examples illustrate the preparation of gamma-pyrones and various intermediates according to the invention.

In the examples where the spectral data are given. NMR chemical changes are reported in the conventional literature.

s = singlet d - void c = triplet y - quartet in = multiplet br = wide.

Example 1

Preparation of 4-Bromo-6-hydroxy-2-methyl-2H-pyran-3 (6H) -one to a solution of g- (2-furyl) ethanol in 125 ml of tetrahydrofuran in 125 ml of water at 0-5 ° C 2.2 equivalents of bromine are added dropwise. The temperature is maintained between 5 ° C and 10 ° C during the addition. After the addition of bromine, the solution was stirred at room temperature for 30 minutes. and adjust the pH to 2.1 with 2N sodium hydroxide solution. The reaction mixture was extracted with ethyl acetate (3 x 100 mL). The ethyl acetate extracts were combined, dried over anhydrous magnesium sulfate, filtered and evaporated to dryness. The residue was chromatographed on silica gel. eluting with 95: 5 chloroform-ethyl acetate. The resulting orange oil was rechromatographed on silica gel, eluting also with 95: 5 chloroform-ethyl acetate.

NMR (CDCl 3, delta):

7.3 (1H. D) 5.6 (1H. D), 4.7-5.0 (1H, q), 1.11.5 (3H. M).

Example 2 Preparation of Compounds of Formula V

The procedure described in Example 1 is repeated with furfuryl alcohol derivatives of general formula (VI) to give compounds of general formula (V) wherein R is hydrogen or ethyl.

Ethyl Compound: 4-Bromo-6-hydroxy-2-ethyl-2H-pyran 3 (6H) -one.

NMR fCDCl ₃ . delta):

7.4 (1H, d), 4.6 4.9 (1H, m), 1.8-2.2 (211 m),

1.0 1.3 (3H.t).

Hydrogen Compound: 4-Bromo-6-hydroxy-2H-pyran-3 (6H) -one.

NMR (CDCl 3, delta):

7.4 (111, d), 5.5 (1H, d), 4.6 (211, dd).

Example 3 Preparation of Compounds of Formula (I)

The procedure described in Example 1 is repeated, but chlorine is substituted for bromine and the corresponding furfuraldehyde alcohols are used. In this way, the following compounds of formula (Π) are prepared:

Methyl: 4 chloro-6-hydroxy-2-methyl-2H-pyran-3 (6H, -one NMR ((TXI ₃ delta)):

7.1 (111d). 5.8 flU, d). 4.6 5.0 (1H. Ni) .4.40 (1H.br.s), 1.2-1.5 (311. M).

Ethyl: 4-chloro-6-hydroxy-2-ethyl-2H-pyran-3 (6H) on.

NMR (CDCl3, delta):

7.0-7.1 (111, (1) .5.6 6.0 (2H, m), 4.4-5.0 (111.Pl). 1.6 2.1 (2H, m), 0.9 1.1 (3H, t).

Hydrogen: 4-chloro-6-hydroxy-2H-pyran-3 (6H) -one NMR (CDCH delta):

7.1 -7.2 (111, d). 5.6 (1H, d).

4.4 -4.9 (2H, dd). (D ₂ O).

Example 4

Preparation of 4-Chloro-6-methoxy-2-diethyl-2H-pyran-3 (6H) -one

To a solution of 0.05 mol of 6-methoxy-2-methyl-2H-pyran 3 (6H) -one in 70 ml of dichloromethane is added 0.05 mol of chlorine gas through a gas inlet at -10 ° C. Triethylamine (0.05 mol) was then added slowly and the temperature was maintained at -10 ° C. The reaction mixture was stirred for 30 minutes, allowed to warm to room temperature, and the resulting triethylamine hydrochloride was filtered off and the solvent was evaporated in vacuo. The crude product was redissolved in a minimal amount of ether benzene (1: 1) and the traces of triethylamine hydrochloride still present. The solvent was evaporated to give 4-chloro-6-methoxy-2-methyl-2H-pyran-3 (6H) -one.

Yield: 99%.

NMR analysis of the signals at 5.05-5.25 shows two doublet doublets at a ratio of 3: 1, corresponding to the proton at the 6 carbon atoms of the two possible isomers of the compound. Both optical forms of the trans isomer were synthesized from the carbohydrate precursor Eberstein and Koebenick (Tetrahedron Letters, 4377 (1974)).

Example 5

For the preparation of 4-bromo-6-methoxy-2-methyl-2H-pyran-3 (6H) -one

The procedure of Example 4 is repeated, but chlorine is replaced by bromine to give 4 bromo-6-methoxy-2-methyl-2H-pyran-3 (6H) -one in 93% yield. Two optical forms of the trans isomer were synthesized by Paulsen et al., Tetrahedron Letters, 4377 (1974).

Example 6

4-Bromo-6-acetyl-2H-pyran-3 (6H) -one

A solution of 6-acetyl-2H-pyran-3 (6H) -one in dichloromethane prepared according to Tetrahedron Letters, 27, 1973 (1971) was brominated as described in Example 5. This gives 4-bromoacetyl 2H-pyran 3 (6H) -one, m.p. 78-80 ° C. The mass spectrum of the compound shows peaks at 234 and 236 units.

Example 7

For the preparation of 4-bromo-6-ethyl-2-methyl-2H-pyran-3 (6H) -one

The procedure described in Example 6 was repeated with N-acetyl-2-methyl-2H-pyran-3 (6H) -one to give 4 bromo-6-acetyl-2-methyl-2H-pyran-3 (6H) - which shows peaks at 249,960 and 247.96 masses by mass spectroscopy.

186 026

NMR (CDCl3b delta): 7.3 (1H, d). 6.4 (1H. Dd), 4.7 (1H. Q). 2.2 (311, s), 1.4 (3H, s).

Claims (1)

Process for the preparation of 4-halo-dihydropyran-3-one derivatives of the formula (J) - in the formula (I) R is hydrogen or C1-C4 alkyl; R 'is C1-C4 alkyl. or a group of the formula -COR wherein R is methyl or ethyl, and X is a chlorine or bromine atom, characterized in that a dihydropyran-3-one derivative of formula II, wherein R and R 'are as defined above, is present in the presence of a solvent at a temperature of from -50 ° C to 50 ° C. with at least one equivalent of chlorine or bromine. 6 pieces of figure National Office of Invention l. K: lliiner Zoltán