SE452616B - PROCEDURE FOR PREPARATION OF 4-HALO-2H-PYRANE-3 (6H) -ON COMPOUNDS - Google Patents

Description

452,616 Synthesis of gamma-pyrones, such as pyromeconic acid, maltol, ethyl-maltol and other 2-substituted 3-hydroxy-gamma-pyrones are described in U.S. Pat. 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.

Malt oil and ethyl maltol enhance the aroma and taste of a variety of food products. These compounds were also used as components in perfumes and essences. The 2-alkenylpyromeconic acids disclosed in U.S. Pat. No. 3,644,635 and the 2-arylmethylpyromeconic acids described in U.S. Pat. flavor enhancers in perfumes.

Patent no. 7707035-7 (publ. No. 433 079) relates i.a. a process for the preparation of a gamma-pyrone of the formula: (I) which comprises heating in acidic aqueous solution, preferably at a temperature in the range of 70-160 ° C, until the hydrolysis is substantially complete, of a 4-halopyron. dihydropyran of formula (II): 452 616 wherein R is hydrogen or alkyl of 1-4 carbon atoms, R 'is hydrogen, alkyl of 1-4 carbon atoms or -COR ", wherein R" is methyl, ethyl or phenyl, R "'is hydrogen or alkyl of 1-4 carbon atoms, and X is chlorine or bromine.

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

More particularly, the present invention relates to a process for the preparation of a 4-halo-dihydropyran compound of the formula (II): wherein R is methyl or ethyl, R 'is methyl or acetyl, R "' is hydrogen and X is chlorine or bromine, which is characterized by bringing a compound of the formula: wherein R, R 'and R "'has the meaning given above, to react 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, 452,616 subchloric acid , subbrakic acid or mixtures thereof, until the reaction is substantially complete.

Examples of suitable solvents for this reaction are water, an alkanol or diol having 1-4 carbon atoms, preferably methanol, an 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 intermediate compound of formula (IV) above can be prepared by bringing a furfuryl alcohol of the formula: c || LR (III) wherein R and R "'have the meaning given above, to react in aqueous solution with at least one equivalent of a halogen-containing oxidant, selected from chlorine, bromine, bromine chloride, hypochlorous acid, subbromic acid or mixtures thereof, in a temperature of -SO to 50 ° C, preferably at room temperature, until the reaction is substantially complete The reaction may be carried out in the presence of a cosolvent, which may suitably be one of the abovementioned solvents for the preparation of the intermediate compound of formula (II) .

If desired, the intermediate 4-halo-dihydropyran compound of formula (II) may be prepared directly from a suitable furfuryl alcohol of formula (III) by reacting the latter in a solvent at a temperature of -50 to 50 ° C, with at least two equivalents of one of the abovementioned halogen-containing oxidants until the reaction is substantially complete. In each of the reactions described above, the preferred halogen-containing oxidant is chlorine or bromine chloride.

The halogen-containing oxidant is selected from chlorine, bromine, bromine chloride, hypochlorous acid or subbromic acid or mixtures 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 chloride.

Underchloric acid and subbromic acid can be conveniently formed in situ by the addition of aqueous acid (HCl, H 2 SO 4 or HBr) to a solution of an alkali metal or alkaline earth metal hypohalite, e.g. NaOCl, KOCl or Ca (OCl) 2.

The preferred halogen-containing oxidants, based on cost factors, are chlorine and bromine chloride produced in situ.

A 6-alkoxy-2H-pyran-3 (6H) -one of formula (IV) above can be prepared according to the method described in Tetrahedron Letters no. 17, 1363-1364 (1976). A furfuryl alcohol is anoxylated anodically to 2- (1-hydroxyalkyl) -2,5-dialkoxy-dihydrofuran.

Treatment with a strong organic acid gives the desired 6-alkoxy compound. A 6-acyl compound can be prepared by conventional treatment of the 6-hydroxy compound with the corresponding anhydride in the presence of pyridine.

According to one embodiment of the invention, a 6-acyl- or 6-alkoxy-2H-pyran-3 (6H) -one is dissolved in a solvent selected from water, ethers, C 1 -C 4 alkanols or diols or low molecular weight ketones, nitriles, esters or amides. The preferred solvent is methanol. An equivalent of a halogen-containing oxidant selected from chlorine, bromine, bromine chloride, hypochlorous acid, subbromic acid or mixtures thereof is added and the 4-halo-dihydropyran is prepared and isolated by carrying out the halogenation at a temperature of -20 to 20 ° C. preferably 5-10 ° C, in the presence of an organic base such as triethylamine. After about 30 minutes, the mixture is allowed to warm to room temperature, then it is filtered to remove triethylamine hydrochloride and the solvent is removed in vacuo to give 4-halo-dihydropyran.

The following examples illustrate the preparation of the intermediate 4-halo-6-substituted dihydropyran compounds according to the process of the invention.

In the examples in which spectral data are mentioned, NMR chemical data are given in accordance with conventional symbols in the literature and all shifts are expressed as 6 units of tetramethylsilane: s = singlet d = doublet q = quartet Example 1 4-chloro-6-methoxy-2- Methyl-2H-pyran-3 (6H) -one To a solution of 6-methoxy-2-methyl-2H-pyran-3 (6H) -one (0.05 mol) in 70 ml of dichloromethane at -10 ° C was added chlorine ( 0.05 mol) via a gas inlet pipe. After this addition, triethylamine (0.05 mol) was added slowly while maintaining the temperature at -10 ° C. After stirring for 30 minutes, the mixture was allowed to warm to room temperature, filtered to remove triethylamine hydrochloride and the solvent removed in vacuo.

Re-dissolution of the crude product in ether / benzene and filtration removed the last traces of triethylamine hydrochloride.

Removal of the solvent gave 4-chloro-6-methoxy-2-methyl-2H-pyran-3 (6H) -one (yield 99%). NMR analysis of the signals at 5.05 to 5.25 clearly showed two doublets in the ratio of 3 to 1 corresponding to the proton at C-6 in the two possible isomers of the compound. Both optical forms of the trans isomer had been synthesized from a carbohydrate precursor compound by Paulsen, Eberstein and Koebernick, Tetrahedron Letters 4377 (1974).

Example 2 4-Bromo-6-methoxy-2-methyl-ZH-pyran-3 (6H) -one The experiment of Example 1 was repeated replacing chlorine with bromine to give 4-bromo-6-methoxy-2-methyl- 2H-pyran-3 (6H) -one in 93% yield. The two optical forms of the trans 452 616 isomer had been synthesized by Paulsen et al., Tetrahedron Letters 4377 (1974).

Example 3 The experiments in Example 1 resp. 2 was repeated starting from a compound of the formula: wherein R is hydrogen or alkyl of 2-4 carbon atoms and R 'is alkyl of 2-4 carbon atoms to give a compound of the formula: wherein R and R' have the meaning given above; and X is chlorine or bromine.

Example 4 4-Bromo-6-acetoxy-2H-pyran-3 (6H) -one A solution in dichloromethane of 6-acetyl-2H-pyran-3 (6H) -one, prepared according to the method of Tetrahedron Letters eel, 1973 (1971), brominated according to Example 6 to give 4-bromo-6-acetoxy-2H-pyran-3 (6H) -one, m.p. 78-80 ° C. The mass spectrum of the compound showed the expected parent peaks at 234 and 236 mass units.

Example 5 4-Bromo-6-acetoxy-2-methyl-2H-pyran-3 (6H) -one The experiment of Example 4 was repeated with 6-acetyl-2-methyl-2H-pyran-3 (6H) -one to give of 4-bromo-6-acetoxy-2-452,616 methyl-2H-pyran-3 (6H) -one, which showed parent masses at 249.96 and 257.96 by mass spectroscopy and the following NMR spectrum: <8, cnc13) = 7.3 <1rx, a), 6.4 (in, a of d), 4.7 (in, q), 2.2 (3H, s); 1.4 (3 H, s).

Example 6 The experiment of Example 1 was repeated using chlorine instead of bromine and starting from a compound of the formula: wherein R is methyl or ethyl and R 'is methyl or acetyl, to give a compound of the formula: wherein R and R 'has the meaning given above and X is chlorine.

Claims (5)

452 616 PATENT CLAIMS A process for the preparation of a 4-halo-dihydropyran compound having the formula: X! wherein R is methyl or ethyl, R 'is methyl or acetyl, R "' is hydrogen and X is chlorine or bromine, characterized in that comprises reacting a compound having the formula: // Rf. wherein R, R 'and R "' are as defined above, in a solvent at a temperature of -50 to 50 ° C. ° C with at least one equivalent of a halogen-containing oxidant consisting of chlorine, bromine, bromine chloride, hypochlorous acid, subbromic acid or a mixture thereof until the reaction is substantially complete. Process according to Claim 1, characterized in that the solvent is water, an alkanol or diol having 1 to 4 carbon atoms, an ether having 2 to 10 carbon atoms or a low molecular weight ketone, nitrile, ester or amide. 452 616 10 3. A process according to claim 2, characterized in that the solvent is methanol, tetrahydrofuran, isopropyl ether or acetone. 4. A process according to any one of the preceding claims, characterized in that the halogen-containing oxidant is chlorine or bromine chloride. 5. A process according to any one of the preceding claims, characterized in that R is ethyl and that R ', R "' and X have the meaning given in claim 1.