NL8105537A - Gamma-pyrones prepn. esp. from furfuryl alcohol cpds. - giving prods. useful in perfume and flavouring field - Google Patents

Abstract

Prepn. of a gamma pyrole of formula (I) comprises heating a 4-halo-dihydropyran of formula (II) or an 6,6'-oxy-bis 4-halo-2H-pyran-3(6H)-one of formula (V) in an aq. acid soln. until hydrolysis is practically complete. (where R is H, 1-4C alkyl, phenyl or benzyl; R' is H, 1-4C alkyl or -COR" where R" is methyl, ethyl or phenyl; R'" is H or 1-4C alkyl and X is Cl or Br).

Description

* * - 1 - * * s

Process for the preparation of 4-halo-dihydropyran derivatives.

This invention relates to a process for the preparation of new 4-halo-dihydropyran which can serve as intermediates in the preparation of 3-hydroxy-4-pyron derivatives, starting from appropriate 6-substituted dihydropyran or furfuryl alcohols using halogen containing oxidants.

Maltol (2-methyl-3-hydroxy-4H-pyranon-4) is a naturally occurring substance found in the bark of young Larix trees, pine nuts and chigorei. Early industrial production was effected by destructive distillation of wood. The synthesis of maltol from 3-hydroxy-2- (piperidino-methyl) -1,4-pyron was described by Spielman and Freifelder in J. Am. Chem. Soc., 69, 2908 (1947). Schenck and Spielman, J. Am. Chem. Soc. 67, 2276 (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), described the synthesis of maltol from protected carbohydrate derivatives. Shono and Matsumura, Tetrahedron Letters, no. 17, 1363 (1976), described a five-stage synthesis of maltol from methylfurfuryl alcohol.

The isolation of 6-methyl-2-ethyl-3-hydro-xy-4H-pyranon-4 as one of the characteristic sweet flavor ingredients in refining end molasses was described by Hiroshi Ito in Agr. Biol. Chem. 40 (5), (1976), 827-832. This compound was previously synthesized as described in U.S. Patent 3,468,915.

Syntheses of γ-pyrons, such as pyromeconic acid, maltol, ethylmaltol and other 2-substituted 3-hydroxy-γ-pyrons are described in U.S. Patent 8105537

SrX * * - 2 - at 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.

Maltol and ethyl maltol enhance the taste and aroma of fine foods. In addition, these compounds are used as ingredients in perfumes and essences. The 2-alkenylpyromeconic acids as described in U.S. Patent 3,644,635 and the 2-arylmethylpyromeconic acids as described in U.S. Patent 3,365,469 inhibit the growth of bacteria and fungi and are useful as flavor and aroma enhancers in food and beverage and flavor enhancers in perfumes.

It has been found that compounds of formula 1, wherein R is hydrogen, alkyl of 1 to 4 carbon atoms, phenyl or benzyl, R 'is hydrogen or alkyl of 1 to 4 carbon atoms, R "is hydrogen, alkyl of 1 to 4 carbon - atoms, or the group -C0R'T, where R''1 represents methyl, ethyl or phenyl, and X represents chlorine or bromine, may serve as intermediates in the preparation of 3-hydroxy-4-pyron derivatives, and that they can be prepared by dissolving a compound 20 of formula 2, wherein R, R 'and R "have the meanings given above, in a solvent at a temperature between -50 ° and + 50 ° C (preferably at room temperature). react with at least one equivalent of halogen-containing oxidant, namely chlorine, bromine, bromine chloride, hypochlorous acid and / or hypobromous acid, until the reaction is substantially complete.

Examples of solvents suitable for this reaction are water, alkanols and alkanediols with 1 to 4 carbon atoms (preferably methanol), ethers with 2 to 10 carbon atoms (preferably tetrahydrofuran or diisopropyl ether), low molecular weight ketones (preferably acetone) and low molecular weight nitriles, esters and amides.

The compound of formula 2 itself can be prepared by a furfuryl alcohol of formula 3, 35 in which R and R 'have the meanings given previously, in aqueous solution at a temperature between -50 ° and + 50 ° C (at 8105537% - 3 - preferred room temperature) to react with at least one equivalent of halogen-containing oxidant, i.e. chlorine, bromine, bromine chloride, hypochlorous acid and / or hypobromous acid, until the reaction is substantially complete. The reaction can take place in the presence of a co-solvent, which may very well be one of the above-mentioned co-solvents.

If desired, the 4-halo-dihydro-pyran of the formula 1 can be prepared directly from an appropriate furfuryl alcohol of the formula 3 by the latter in a solvent at a temperature between -50 ° and + 50 ° C with at least two equivalents of the above halogen reacting containing oxidants until the reaction is substantially complete.

The halogen-containing oxidant can be chlorine, bromine, bromine chloride, hypochlorous acid and hypobromous acid, or a mixture thereof. Bromine chloride is a commercially available gas. 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 bromide. Hypochlorous acid and hypobromous acid can conveniently be prepared in situ by adding an aqueous acid (HCl, H 2 SO 4 or HBr) to a solution of an alkali or alkaline earth metal hypohalite (e.g. NaOCl, KCl 3 or CaiOCl 3). Considering the cost, chlorine and bromine chloride prepared in situ are the preferred oxidants.

As indicated above, the 6-hydroxy-2H-pyranone-3 (6H) of formula 2 can be prepared by reacting the appropriate furfuryl alcohol with an equivalent halogen-containing oxidant. The isolated intermediate is readily converted to the desired 4-halogen-6-hydroxy-2H-pyranone-3 (6H) of Formula 1 by reacting it with an equivalent halogen-containing oxidant as previously described.

A 6-alkoxy-2H-pyranon-3 (6H) can be prepared as described in Tetrahedron Letters No. 17 (1976) 1363-1364. A furfuryl alcohol is anodically alkylated to 8105537-4> 2- (1-hydroxyalkyl) -2,5-dialkoxydihydrofuran. Treatment with a strong organic acid then gives the desired 6-alkoxy compound. A 6-acyl compound can be obtained by reacting the 6-hydroxy compound with the appropriate anhydride in the presence of pyridine.

A 6-acyl or 6-alkoxy-2H-pyranone-3 (6H) is dissolved in acetic acid, formic acid, trifluoroacetic acid, halogenated solvent, ether, alkanol or alkanediol with 1 to 4 carbon atoms or a low molecular weight ketone, nitrile, 10 ester or amide. Preferably, the solvent used is acetic acid, formic acid or methanol. An equivalent halogen-containing oxidant is then added at room temperature and the mixture is allowed to react until conversion to 4-halo-dihydropyran is substantially complete.

If desired, the 4-halo-dihydropyran can be prepared and isolated by halogenation at a temperature between -20 ° and + 20 ° C, preferably between 5 ° and 10 ° C, in the presence of an organic base such as triethyl amine from to feed. After about 30 minutes, the reaction mixture is allowed to warm to room temperature, the triethylammonium chloride is filtered and the solvent is removed in vacuo to give the 4-halo-dihydropyran.

In the following examples, the first three illustrate the preparation of compounds of formula 1 directly from a furfuryl alcohol without prior isolation of the intermediate of formula 2. Where NMR data are reported, the usual symbols are used and all peak shifts are reported as δ units relative to tetramethyl silane; 30 s = singlet d = doublet t = triplet q - quartet m = multiplet and 35 br = wide.

8105537 - 5 - *

Example I

4-bromo-6-hydroxy-2-methyl-2H-pyranone-3 (6H)

To a solution of 25 g of 1- (α-puryl) ethanol in 125 ml of tetrahydrofuran and 125 ml of water cooled to 0-5 ° C was added dropwise 2.2 equivalents of bromine, the temperature being between 5 ° and 10 ° C was held. After all the bromine was added, the solution was stirred at room temperature for an additional 30 minutes, then the pH was adjusted to 2.1 with 2N NaOH. The reaction mixture was extracted with 3 x 100 10 ml ethyl acetate, and the combined ethyl acetate extracts were dried over HgSO 4, filtered and evaporated to dryness. The residue was chromatographed on silica gel with chloroform / ethyl acetate 95: 5 as the running liquid. The product was an orange oil which was further chromatographed on silica gel with chloroform / ethyl acetate 95: 5.

NMR (in CDCl 3, S) 7.3 (1H, d), 5.6 (1H, d), 4.7-5.0 (1H, q), 1.1-1.5 (3H, m) .

Example II

Example I was repeated starting from furfuryl alcohol and α-ethyl furfuryl alcohol to give two compounds of formula 1 wherein R 1 was always hydrogen and X was bromine and R was hydrogen and ethyl, respectively.

The hydrogen compound: NMR (in CDCl 3, 5) 7.4 (1H, d), 5.5 (1H, d), 4.6 (2H, d of d).

The ethyl compound: NMR (in CDCl 3, <5) 7.4 (1H, d), 4.6-4.9 (1H, m), 1.8-2.2 (2H, m), 1 .0-1.3 (3H, t).

Example III

The procedure of Example I was repeated starting from the appropriate furfuryl alcohols and with chlorine instead of bromine. This gave the following compounds: 4-chloro-6-hydroxy-2-methyl-2H-pyranone-3 (6H) NMR (in CDCl 3, θ) 7.1 (1H, d), 5.8 (1H, d) , 4.6-5.0 (1H, m), 4.4 (1H, br.s.), 1.2-1.5 (3H, m).

35 4-chloro-6-hydroxy-2-ethyl-2H-pyranone-3 (6H) 8105537 7 * t * - 6 - NMR (in CDCl3, δ) 7.0-7.1 (1H, d), 5 .6-6.0 (2H, m), 4.4-5.0 (1H, m), 1.6-2.1 (2H, m), 0.9-1.1 (3H, t) .

4-chloro-6-hydroxy-2H-pyranon-3 (6H) NMR (in CDCl 3, δ) 7.1-7.2 (1H, d), 5.6 (1H, d), 4.4-4 1.9 (2H, 5d of d) (D 2 O added).

Example IV

4-chloro-6-methoxy-2-methyl-2H-pyranone-3 (6H)

To a solution of 0.05 gmole of 6-methoxy-2-methyl-2H-pyranone-3 (6H) cooled to -10 ° C in 70 ml of dichloromethane was added 0.05 gmole of chlorine through a gas-introduction tube. After this, 0.05 gmole triethylamine was slowly added, keeping the temperature at -10 ° C. After stirring for 30 minutes, the reaction mixture was allowed to warm to room temperature, the triethylammonium chloride was filtered off and the solvent was removed in vacuo. The crude product was taken up in ether / benzene and filtered to remove the last residue of triethylammonium chloride. Removal of the solvent gave 4-chloro-6-methoxy-2-methyl-2H-pyranone-3 (6H) in 99% yield. In the NMR spectrum, the 20 signals at 5.05 and 5.25 ppm clearly showed two doublets in a ratio of 3: 1 due to the proton at C-6 of the two possible isomers. Both optical forms of the trans isomer were formerly prepared from a carbohydrate by Paulsen, Eberstein and Koebernick, see Tetrahedron Letters 25 i5 (1974) 4377.

Example V

4-b room-6-m thoxy-2-m thy1-2H-pyranón-3 (6H)

Example IV was repeated with chlorine instead of bromine to give 4-bromo-6-methoxy-30 2-methyl-2H-pyranone-3 (6H) in 93% yield. The two optical forms of the trans isomer were previously prepared by Paulsen and co-workers, see the aforementioned article in Tetrahedron Letters.

Example VI

4-Bromo-6-acetyl-2H-pyranone-3 (6H) 35 A solution of 6-acetyl-2H-pyranone-3 (6H), prepared as described in Tetrahedron 27 (1971) 1973, 8105537 o-7 - was brominated in accordance with Example I, adding 4-bromo-6-acetyl-2H-pyranone-3 (6H) with mp. 78-80 ° C. The mass spectrum of this compound showed the expected peaks at 234 and 236 mass units.

5 Example Vil 4-bromo-6-acetyl-2-methyl-2H-pyranone-3 (6H)

Example VI was repeated starting from 6-acetyl-2-methyl-2H-pyranone-3 (6H) to give the 4-bromo-6-acetyl-2-methyl-2H-pyranone-3 (6H) with peaks at 250 and 248 mass-10 units and with the following NMR spectrum (in CDCl ^): 7.3 (1H, d), 6.4 (1H, d of d), 4.7 (1H, q), 2.2 (3H s), 1.4 (3H s).

8105537

Claims (3)

A process for the preparation of a compound of formula 1, wherein R is hydrogen, alkyl of 5 to 4 carbon atoms, phenyl or benzyl, R 'is hydrogen or alkyl of 1 to 4 carbon atoms, R "is hydrogen, alkyl of 1 to 4 Represents 4 carbon atoms or the group -COR''1, wherein R ** 'is hydrogen or alkyl of 1 to 4 carbon atoms, and wherein X represents chlorine or bromine, characterized in that a compound according to formula 2, wherein R, R 'and R "have the meanings given above, react in a solvent at a temperature between -5cP and + 50 ° C with at least one equivalent of chlorine, bromine, bromine chloride, hypochlorous acid and / or hypobromous acid until the reaction substantially completely i. 2. Process according to claim 1, characterized in that the solvent is water, an alkanol or alkane diol with 1 to 4 carbon atoms, an ether with 2 to 10 carbon atoms, or a low molecular weight ketone, nitrile, ester or amide. 3. Process according to claim 1 or 2, characterized in that R is ethyl and R "represents alkyl of 1 to 4 carbon atoms or the group -COR" wherein R "is methyl, ethyl or phenyl. 8105537